RAD51 inhibitors

ABSTRACT

This application is directed to inhibitors of RAD51 represented by the following structural formula,and methods for their use, such as to treat cancer, autoimmune diseases, immune deficiencies, or neurodegenerative diseases.

RELATED APPLICATION

This application claims priority to, and the benefit of U.S. ProvisionalApplication No. 62/816,998, filed on Mar. 12, 2019, the entire contentsof which are incorporated by reference.

BACKGROUND

RAD51 is a member of the RAD51 family which promotes the repair of DNAdouble strand breaks (DSB). RAD51 protein is highly conserved in mosteukaryotes, from yeast to humans. The human RAD51 is a 339-amino acidprotein that plays a major role in DNA replication and repair byhomologous recombination (HR). RAD51 catalyzes strand transfer between abroken sequence and undamaged homologous template to allow re-synthesisof the damaged region.

Studies have demonstrated sensitization to certain DNA damagingtherapies associated with defects in proteins that promote HR DNArepair. This sensitization is particularly dramatic for DNAcross-linking chemotherapeutic drugs and ionizing radiation. It has beenshown that HR can be partially inhibited in order to sensitize cells toDNA damaging therapies. For example, inhibition of XRCC3 (a RAD51paralog protein) using a synthetic peptide sensitized Chinese HamsterOvary (CHO) cells to cisplatin and inhibited the formation ofsub-nuclear RAD51 foci in response to DNA damage. Researchers haveinhibited the expression of the RAD51 protein itself or blocked itsfunction by over-expressing a dominant negative BRC peptide fragmentderived from BRCA2. In view of the connection between increasedsensitivity to DNA damaging therapies and defects in HR DNArepair-related proteins, there is a need for compounds that inhibitRAD51. The present application addresses the need.

SUMMARY

The present application relates to a compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein thedefinition of each variable is provided herein below.

The present application also relates to a pharmaceutical compositioncomprising a compound disclosed herein or a pharmaceutically acceptablesalt or solvate thereof and a pharmaceutically acceptable carrier ordiluent.

The present application further relates to a method of treating adisease or disorder in which RAD51 plays a role, for example, cancer, anautoimmune disease, an immune deficiency, or a neurodegenerativedisease. The method comprises administering to a subject in need thereofan effective amount of a compound disclosed herein or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositiondisclosed herein.

The present application further relates to use of a compound disclosedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of a disease or disorder in which RAD51plays a role, for example, a cancer, an autoimmune disease, an immunedeficiency, or a neurodegenerative disease.

The present application further relates to a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, for use in treating adisease or disorder in which RAD51 plays a role, for example, a cancer,an autoimmune disease, an immune deficiency, or a neurodegenerativedisease.

The present application further relates to use of a compound disclosedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating a disease ordisorder in which RAD51 plays a role, for example, a cancer, anautoimmune disease, an immune deficiency, or a neurodegenerativedisease.

The present application provides compounds and compositions with animproved efficacy and safety profile relative to known RAD51 inhibitors.The present application also provides agents with novel mechanisms ofaction toward RAD51 in the treatment of various types of diseases.Ultimately the present application provides a novel therapeutic strategyfor the treatment of diseases and disorders associated with RAD51.

The details of the application are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent application, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the applicationwill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this application belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

DETAILED DESCRIPTION

Compounds of the Application

In one aspect, the present application relates to a compound of FormulaI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

the thiazolyl ring

is optionally substituted with F or Cl;

the ring Cy is C₃-C₇ cycloalkyl, bridged C₆-C₁₂ cycloalkyl, or saturatedheterocyclyl comprising one or two 3- to 7-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the cycloalkyl orheterocyclyl moiety is optionally substituted with one or more groupsselected from halogen, OH, CN, NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and C₁-C₄ haloalkoxy;

X₁ is NR₈ or O, or, when X₁ is bonded to a nitrogen atom in the ring Cy,X₁ is absent;

X₂ is NR₈ or O;

R₁ is H or C₁-C₆ alkyl optionally substituted with halogen, OH, C₁-C₆alkoxy, or C₆-C₁₀ aryloxy;

R₂ is H or C₁-C₆ alkyl optionally substituted with halogen, OH, C₁-C₆alkoxy, or C₆-C₁₀ aryloxy;

or R₁ and R₂, together with the nitrogen atom to which they areattached, form a heterocyclyl comprising one or two 3- to 7-memberedrings and 1-3 heteroatoms selected from N, O, and S;

R₃ is C₁-C₆ alkyl optionally substituted with one or more groupsselected from halogen, OH, and CN, phenyl, CH₂-phenyl, C₃-C₇ cycloalkyl,CH₂—(C₃-C₇) cycloalkyl, heterocyclyl, or CH₂-heterocyclyl, wherein theheterocyclyl comprises one or two 3- to 7-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the cycloalkyl, phenyl,or heterocyclyl moiety is optionally substituted with one or more groupsselected from halogen, OH, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and C₁-C₄ haloalkoxy;

A₁, A₂, A₃, and A₄ are each independently N or C(R₄);

each R₄ is independently H, halogen, CN, OH, N(R₆′)₂, C₁-C₆ alkoxy,C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, Q-T, C₆-C₁₀ aryl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl moiety isoptionally substituted with one or more R₉;

each Q is independently C₁-C₄ alkylene or O—(C₁-C₄) alkylene wherein theoxygen atom is bonded to the ring

each T is independently C₁-C₄ alkoxy, OH, N(R₆)₂, N(R₅)C(═O)R₆,N(R₅)C(═O)OR₆, C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the aryl or heteroarylmoiety is optionally substituted with one or more R₉;

each R₅ is independently H or C₁-C₄ alkyl;

each R₆′ is independently H, C₁-C₆ alkyl optionally substituted with oneor more R₇, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, heterocyclyl comprisingone or two 3- to 7-membered rings and 1-3 heteroatoms selected from N,O, and S, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S, whereinthe cycloalkyl, heterocyclyl, aryl, or heteroaryl moiety is optionallysubstituted with one or more R₉, wherein at least one R₆′ is not H;

or two R₆′ together with the atoms to which they are attached form a 3-to 10-membered heterocyclyl comprising 1-3 heteroatoms selected from N,O, and S, wherein the heterocyclyl is optionally substituted with one ormore R₉;

each R₆ is independently H, C₁-C₆ alkyl optionally substituted with oneor more R₇, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or heteroaryl comprising oneor two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O,and S, wherein the aryl or heteroaryl moiety is optionally substitutedwith one or more R₉;

or two R₆ together with the atoms to which they are attached form a 3-to 10-membered heterocyclyl comprising 1-3 heteroatoms selected from N,O, and S, wherein the heterocyclyl is optionally substituted with one ormore R₉;

each R₇ is independently N(R₈)₂, OR₈, C₆-C₁₀ aryl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S;

each R₈ is independently H or C₁-C₆ alkyl; and

each R₉ is independently oxo, halogen, OH, CN, NH₂, N(C₁-C₄ alkyl)₂,C₁-C₆ alkyl, N(C₁-C₄ alkyl)₂, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy, wherein the C₁-C₆ alkyl is optionally substituted with oneor more oxo, OH, O(C₁-C₄ alkyl), CN, NH₂, NH(C₁-C₄ alkyl), or N(C₁-C₄alkyl)₂.

In one aspect, the present application relates to a compound of FormulaI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

the thiazolyl ring

is optionally substituted with F or Cl;

the ring Cy is C₃-C₇ cycloalkyl, bridged C₆-C₁₂ cycloalkyl, or saturatedheterocyclyl comprising one or two 3- to 7-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the cycloalkyl orheterocyclyl moiety is optionally substituted with one or more groupsselected from halogen, OH, CN, NH₂, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and C₁-C₄ haloalkoxy;

X₁ is NR₈ or O, or, when X₁ is bonded to a nitrogen atom in the ring Cy,X₁ is absent;

X₂ is NR₈ or O;

R₁ is H or C₁-C₆ alkyl optionally substituted with halogen, OH, C₁-C₆alkoxy, or C₆-C₁₀ aryloxy;

R₂ is H or C₁-C₆ alkyl optionally substituted with halogen, OH, C₁-C₆alkoxy, or C₆-C₁₀ aryloxy;

or R₁ and R₂, together with the nitrogen atom to which they areattached, form a 3-7 membered heterocyclic ring comprising 1 or 2heteroatoms selected from N, O, and S;

R₃ is C₁-C₆ alkyl optionally substituted with one or more groupsselected from halogen, OH, and CN, phenyl, CH₂-phenyl, C₃-C₇ cycloalkyl,CH₂—(C₃-C₇) cycloalkyl, heterocyclyl, or CH₂-heterocyclyl, wherein theheterocyclyl comprises one 3- to 7-membered ring and 1 or 2 heteroatomsselected from N, O, and S, wherein the cycloalkyl, phenyl, orheterocyclyl moiety is optionally substituted with one or more groupsselected from halogen, OH, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and C₁-C₄ haloalkoxy;

A₁, A₂, A₃, and A₄ are each independently N or C(R₄);

each R₄ is independently H, halogen, CN, OH, N(R₆′)₂, C₁-C₄ alkoxy,C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, Q-T, C₆-C₁₀ aryl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl moiety isoptionally substituted with one or more R₉;

each Q is independently C₁-C₄ alkylene or O—(C₁-C₄) alkylene wherein theoxygen atom is bonded to the ring

each T is independently C₁-C₄ alkoxy, NH₂, NH(C₁-C₄ alkyl), N(C₁-C₄alkyl)₂, N(R₅)C(═O)R₆, N(R₅)C(═O)OR₆, C(═O)N(R₆)₂, C(═O)OR₆, or C(═O)R₆;

each R₅ is independently H or C₁-C₄ alkyl;

each R₆′ is independently H, C₁-C₆ alkyl optionally substituted with oneor more R₇, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or heteroaryl comprising oneor two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O,and S, wherein the aryl or heteroaryl moiety is optionally substitutedwith one or more R₉, wherein at least one R₆′ is not H;

each R₆ is independently H, C₁-C₆ alkyl optionally substituted with oneor more R₇, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or heteroaryl comprising oneor two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O,and S, wherein the aryl or heteroaryl moiety is optionally substitutedwith one or more R₉;

each R₇ is independently N(R₈)₂ or OR₈;

each R₈ is independently H or C₁-C₆ alkyl; and

each R₉ is independently OH, CN, NH₂, N(C₁-C₄ alkyl)₂, C₁-C₆ alkyloptionally substituted with one or more groups selected from OH, CN,NH₂, and N(C₁-C₄ alkyl)₂, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, or C₁-C₆haloalkoxy.

In some embodiments, the compound of Formula I is of Formula Ia or Ib:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula I is of Formula Ic:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula I is of Formula Id, Ie, If,or Ig:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula I is of Formula IIa or IIb:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula I is of Formula IIc:

or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the compound of Formula I is of Formula IId, IIe,IIf, or IIg:

or a pharmaceutically acceptable salt or solvate thereof.

For a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, IIa,IIb, IIc, IId, IIe, IIf, or IIg, where applicable:

(A1) In some embodiments, the thiazolyl ring

is unsubstituted.

(A2) In some embodiments, the thiazolyl ring

is substituted with F.

(A3) In some embodiments, the thiazolyl ring

is substituted with Cl.

(B1) In some embodiments, the ring Cy is C₃-C₇ cycloalkyl selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, eachof which is optionally substituted with one or more groups selected fromhalogen (e.g., F, Cl, Br, or I), OH, CN, NH₂, C₁-C₄ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), C₁-C₄haloalkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, or t-butyl, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy), and C₁-C₄ haloalkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)). In some embodiments, the ring Cy iscyclohexyl, optionally substituted as described herein.

(B2) In some embodiments, the ring Cy is bridged C₆-C₁₂ cycloalkylselected from bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl,bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl,6,6-dimethylbicyclo[3.1.1]heptyl, and adamantyl, each of which isoptionally substituted with one or more groups selected from halogen(e.g., F, Cl, Br, or I), OH, CN, NH₂, C₁-C₄ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), C₁-C₄haloalkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, or t-butyl, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy), and C₁-C₄ haloalkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)).

(B3) In some embodiments, the ring Cy is saturated heterocyclyl selectedfrom aziridinyl, oxiranyl, thiiranyl, diaziridinyl, oxaziridinyl,dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl,dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolany, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl,azepanyl, oxepanyl, thiepanyl, diazepanyl, diazaspiro[4.4]nonyl,diazaspiro[3.5]nonyl, hexahydropyridazinyl, hexahydropyrimidinyl,tetrahydrothiopyranyl, thiomorpholinyl, tropanyl, valerolactamyl,azanorbornyl, quinuclidinyl, isoquinuclidinyl,azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.1]octanyl,azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl,azabicyclo[3.3.0]nonanyl, azabicyclo [3.3.1]nonanyl,diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.2.1]octanyl,octahydropyrrolo[3,4-b]pyrrolyl, and octahydropyrrolo[3,4-c]pyrrolyl,each of which is optionally substituted with one or more groups selectedfrom halogen (e.g., F, Cl, Br, or I), OH, CN, NH₂, C₁-C₄ alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, ort-butyl), C₁-C₄ haloalkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, or t-butyl, each of which is substituted withone or more halogen (e.g., F, Cl, Br, or I)), C₁-C₄ alkoxy (e.g.,methoxy, ethoxy, propoxy, or butoxy), and C₁-C₄ haloalkoxy (e.g.,methoxy, ethoxy, propoxy, or butoxy, each of which is substituted withone or more halogen (e.g., F, Cl, Br, or I)).

(C1) In some embodiments, X₁ is NR₈ and X₂ is NR₈. In a furtherembodiment, each R₈ is H. In another further embodiment, one R₈ is H,and the other R₈ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched)). In another furtherembodiment, each R₈ is independently C₁-C₆ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), or hexyl (straight or branched)).

(C2) In some embodiments, X₁ is NR₈ and X₂ is O. In a furtherembodiment, R₈ is H. In another further embodiment, R₈ is C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl (straight or branched), or hexyl (straight orbranched)).

(C3) In some embodiments, X₁ is O and X₂ is NR₈. In a furtherembodiment, R₈ is H. In another further embodiment, R₈ is C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl (straight or branched), or hexyl (straight orbranched)).

(C4) In some embodiments, X₁ is O and X₂ is O.

(C5) In some embodiments, X₁ is absent and X₂ is NR₈. In a furtherembodiment, R₈ is H. In another further embodiment, R₈ is C₁-C₆ alkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl (straight or branched), or hexyl (straight orbranched)).

(C6) In some embodiments, X₁ is absent and X₂ is O.

(D1) In some embodiments, R₁ is H.

(D2) In some embodiments, R₁ is C₁-C₆ alkyl selected from methyl, ethyl,n-propyl, propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), and hexyl (straight or branched), each of which isoptionally substituted with one or more groups selected from halogen(e.g., F, Cl, Br, or I), OH, C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propoxy, butoxy, pentoxy, or hexyloxy), and C₆-C₁₀ aryloxy (e.g.,phenoxy). In some embodiments, R₁ is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, eachof which is optionally substituted with one or more groups selected fromhalogen (e.g., F, Cl, Br, or I), OH, C₁-C₆ alkoxy (e.g., methoxy,ethoxy, propoxy, butoxy, pentoxy, or hexyloxy), and C₆-C₁₀ aryloxy(e.g., phenoxy). In some embodiments, R₁ is C₁-C₄ alkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is optionally substituted with one or more groupsselected from halogen (e.g., F, Cl, Br, or I) and OH. In someembodiments, R₁ is unsubstituted C₁-C₆ alkyl. In some embodiments, R₁ isunsubstituted C₁-C₄ alkyl.

(E1) In some embodiments, R₂ is H.

(E2) In some embodiments, R₂ is C₁-C₆ alkyl selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), and hexyl (straight or branched), each of which isoptionally substituted with one or more groups selected from halogen(e.g., F, Cl, Br, or I), OH, C₁-C₆ alkoxy (e.g., methoxy, ethoxy,propoxy, butoxy, pentoxy, or hexyloxy), and C₆-C₁₀ aryloxy (e.g.,phenoxy). In some embodiments, R₂ is C₁-C₄ alkyl selected from methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl, eachof which is optionally substituted with one or more groups selected fromhalogen (e.g., F, Cl, Br, or I), OH, C₁-C₆ alkoxy (e.g., methoxy,ethoxy, propoxy, butoxy, pentoxy, or hexyloxy), and C₆-C₁₀ aryloxy(e.g., phenoxy). In some embodiments, R₂ is C₁-C₄ alkyl selected frommethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, andt-butyl, each of which is optionally substituted with one or more groupsselected from halogen (e.g., F, Cl, Br, or I) and OH. In someembodiments, R₂ is unsubstituted C₁-C₆ alkyl. In some embodiments, R₂ isunsubstituted C₁-C₄ alkyl.

(DE) In some embodiments, R₁ and R₂, together with the nitrogen atom towhich they are attached, form heterocyclic ring selected fromaziridinyl, oxiranyl, thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl,azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolany, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl,azepanyl, oxepanyl, thiepanyl, diazepanyl, hexahydropyridazinyl,hexahydropyrimidinyl, tetrahydrothiopyranyl, and thiomorpholinyl. Insome embodiments, R₁ and R₂, together with the nitrogen atom to whichthey are attached, form azetidinyl or pyrrolidinyl.

(F1) In some embodiments, R₃ is C₁-C₆ alkyl selected from methyl, ethyl,n-propyl, propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), and hexyl (straight or branched), each of which isoptionally substituted with one or more groups selected from halogen(e.g., F, Cl, Br, or I), OH, and CN. In some embodiments, R₃ is C₁-C₄alkyl selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, and t-butyl, each of which is optionally substituted with oneor more groups selected from halogen (e.g., F, Cl, Br, or I), OH, andCN. In some embodiments, R₃ is unsubstituted C₁-C₆ alkyl. In someembodiments, R₃ is unsubstituted C₁-C₄ alkyl. In some embodiments, R₃ isunsubstituted methyl. In some embodiments, R₃ is unsubstituted i-propyl.In some embodiments, R₃ is unsubstituted t-butyl.

(F2) In some embodiments, R₃ is phenyl or CH₂-phenyl, wherein the phenylmoiety is optionally substituted with one or more groups selected fromhalogen (e.g., F, Cl, Br, or I), OH, CN, C₁-C₄ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), C₁-C₄haloalkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, or t-butyl, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy), and C₁-C₄ haloalkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)).

(F3) In some embodiments, R₃ is C₃-C₇ cycloalkyl or CH₂—(C₃-C₇)cycloalkyl, wherein the cycloalkyl moiety is selected from cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, each of which isoptionally substituted with one or more groups selected from halogen(e.g., F, Cl, Br, or I), OH, CN, C₁-C₄ alkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), C₁-C₄haloalkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, or t-butyl, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)), C₁-C₄ alkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy), and C₁-C₄ haloalkoxy (e.g., methoxy, ethoxy,propoxy, or butoxy, each of which is substituted with one or morehalogen (e.g., F, Cl, Br, or I)). In some embodiments, R₃ is cyclopropylor cyclobutyl, or CH₂-cyclopropyl or CH₂-cyclobutyl, each of which isoptionally substituted as described herein. In some embodiments, R₃ iscyclopropyl optionally substituted as described herein.

(F4) In some embodiments, R₃ is heterocyclyl or CH₂-heterocyclyl,wherein the heterocyclyl moiety is selected from aziridinyl, oxiranyl,thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl,thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolany, piperidinyl, tetrahydropyranyl, thianyl,piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl, azepanyl, oxepanyl,thiepanyl, diazepanyl, hexahydropyridazinyl, hexahydropyrimidinyl,tetrahydrothiopyranyl, and thiomorpholinyl, each of which is optionallysubstituted with one or more groups selected from halogen (e.g., F, Cl,Br, or I), OH, CN, C₁-C₄ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, or t-butyl), C₁-C₄ haloalkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, eachof which is substituted with one or more halogen (e.g., F, Cl, Br, orI)), C₁-C₄ alkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy), and C₁-C₄haloalkoxy (e.g., methoxy, ethoxy, propoxy, or butoxy, each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I)). In someembodiments, R₃ is unsubstituted oxetanyl.

(G1) In some embodiments, A₁, A₂, A₃, and A₄ are each C(R₄).

(G2) In some embodiments, one, two, or three of A₁, A₂, A₃, and A₄ areN, and the remaining of A₁, A₂, A₃, and A₄ are C(R₄).

(G3) In some embodiments, one of A₁, A₂, A₃, and A₄ is N, and theremaining of A₁, A₂, A₃, and A₄ are C(R₄).

(G3a) In some embodiments, A₁ is N, and A₂, A₃, and A₄ are C(R₄).

(G3b) In some embodiments, A₂ is N, and A₁, A₃, and A₄ are C(R₄).

(G3c) In some embodiments, A₃ is N, and A₁, A₂, and A₄ are C(R₄).

(G3d) In some embodiments, A₄ is N, and A₁, A₂, and A₃ are C(R₄).

(G4) In some embodiments, two of A₁, A₂, A₃, and A₄ are N, and theremaining of A₁, A₂, A₃, and A₄ are C(R₄).

(G4a) In some embodiments, A₁ and A₂ are N, and A₃ and A₄ are C(R₄).

(G4b) In some embodiments, A₁ and A₃ are N, and A₂ and A₄ are C(R₄).

(G4c) In some embodiments, A₁ and A₄ are N, and A₂ and A₃ are C(R₄).

(G4d) In some embodiments, A₂ and A₃ are N, and A₁ and A₄ are C(R₄).

(G4e) In some embodiments, A₂ and A₄ are N, and A₁ and A₃ are C(R₄).

(G4f) In some embodiments, A₃ and A₄ are N, and A₁ and A₂ are C(R₄).

(G5) In some embodiments, three of A₁, A₂, A₃, and A₄ are N, and theremaining of A₁, A₂, A₃, and A₄ is C(R₄).

(G5a) In some embodiments, A₂, A₃, and A₄ are N, and A₁ is C(R₄).

(G5b) In some embodiments, A₁, A₃, and A₄ are N, and A₂ is C(R₄).

(G5c) In some embodiments, A₁, A₂, and A₄ are N, and A₃ is C(R₄).

(G5d) In some embodiments, A₁, A₂, and A₃ are N, and A₄ is C(R₄).

(G6) In some embodiments, A₁, A₂, A₃, and A₄ are each N.

(G7) In some embodiments, at most two of A₁, A₂, A₃, and A₄ are N.

(H1) In some embodiments, each R₄ is H.

(H2) In some embodiments, at least one R₄ is halogen, CN, OH, N(R₆′)₂,C₁-C₆ alkoxy, C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, Q-T, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the aryl or heteroarylmoiety is optionally substituted with one or more R₉.

(H2a) In some embodiments, at least one R₄ is halogen (e.g., F, Cl, Br,or I), CN, OH, N(R₆′)₂, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy, pentoxy, or hexoxy), C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, or Q-T.

(H2b) In some embodiments, at least one R₄ is CN, OH, N(R₆′)₂, C₁-C₆alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy),C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, or Q-T.

(H2c) In some embodiments, at least one R₄ is C(═O)N(R₆)₂, C(═O)OR₆,C(═O)R₆, or Q-T.

(H2d) In some embodiments, at least one R₄ is Q-T.

(H2e) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇), C₁-C₆ haloalkyl (e.g., methyl, ethyl,n-propyl, propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), or hexyl (straight or branched), each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I)), C₃-C₇cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl), heterocyclyl comprising one or two 3- to 7-membered ringsand 1-3 heteroatoms selected from N, O, and S (e.g., aziridinyl,oxiranyl, thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl, azetidinyl,oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolany, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl,azepanyl, oxepanyl, thiepanyl, diazepanyl, hexahydropyridazinyl,hexahydropyrimidinyl, tetrahydrothiopyranyl, or thiomorpholinyl), C₆-C₁₀aryl (e.g., phenyl), or heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the cycloalkyl,heterocyclyl, aryl, or heteroaryl moiety is optionally substituted withone or more R₉.

(H2e-1) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇), or C₁-C₆ haloalkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl(straight or branched), or hexyl (straight or branched), each of whichis substituted with one or more halogen (e.g., F, Cl, Br, or I)).

(H2e-2) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇).

(H2e-3) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is C₁-C₆ haloalkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), or hexyl (straight or branched), each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I)).

(H2e-4) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is C₃-C₇ cycloalkyl (e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl), wherein thecycloalkyl moiety is optionally substituted with one or more R₉.

(H2e-5) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is heterocyclyl comprising one or two 3- to7-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,aziridinyl, oxiranyl, thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl,azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolany, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl,azepanyl, oxepanyl, thiepanyl, diazepanyl, hexahydropyridazinyl,hexahydropyrimidinyl, tetrahydrothiopyranyl, or thiomorpholinyl),wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is heterocyclyl comprising one 4- to 6-memberedring and 1-3 heteroatoms selected from N, O, and S, as described herein,wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is heterocyclyl comprising one 4- to 5-memberedring and 1-3 heteroatoms selected from N, O, and S, as described herein,wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is heterocyclyl comprising one 4-membered ringand 1-2 heteroatoms selected from N, O, and S, as described herein,wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is heterocyclyl comprising one 4-membered ringand 1 heteroatom selected from N, O, and S, as described herein, whereinthe heterocyclyl moiety is optionally substituted with one or more R₉.

(H2e-6) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is C₆-C₁₀ aryl (e.g., phenyl), wherein the arylmoiety is optionally substituted with one or more R₉.

(H2e-7) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is H, and the other R₆′ is heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, atleast one R₄ is N(R₆′)₂, and one of R₆′ is H, and the other R₆′ isheteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatomsselected from N, O, and S, as described herein, wherein the heteroarylmoiety is optionally substituted with one or more R₉. In someembodiments, at least one R₄ is N(R₆′)₂, and one of R₆′ is H, and theother R₆′ is heteroaryl comprising one 5-membered ring and 1-3heteroatoms selected from N, O, and S, as described herein, wherein theheteroaryl moiety is optionally substituted with one or more R₉. In someembodiments, at least one R₄ is N(R₆′)₂, and one of R₆′ is H, and theother R₆′ is heteroaryl comprising one 6-membered ring and 1-3heteroatoms selected from N, O, and S, as described herein, wherein theheteroaryl moiety is optionally substituted with one or more R₉.

(H2e-8) In some embodiments, at least one R₄ is N(R₆′)₂, and the two R₆′are each independently C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇), or C₁-C₆ haloalkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl(straight or branched), or hexyl (straight or branched), each of whichis substituted with one or more halogen (e.g., F, Cl, Br, or I)).

(H2e-9) In some embodiments, at least one R₄ is N(R₆′)₂, and the two R₆′together with the atoms to which they are attached form a 3- to10-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O,and S (e.g., aziridinyl, oxiranyl, thiiranyl, diaziridinyl,oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl,dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolany,piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl,trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, diazepanyl,hexahydropyridazinyl, hexahydropyrimidinyl, tetrahydrothiopyranyl, orthiomorpholinyl), wherein the heterocyclyl is optionally substitutedwith one or more R₉. In some embodiments, at least one R₄ is N(R₆′)₂,and the two R₆′ together with the atoms to which they are attached forma 3- to 6-membered heterocyclyl comprising 1-3 heteroatoms selected fromN, O, and S, as described herein, and is optionally substituted with oneor more R₉. In some embodiments, at least one R₄ is N(R₆′)₂, and the twoR₆′ together with the atoms to which they are attached form a 4- to6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O,and S, as described herein, and is optionally substituted with one ormore R₉. In some embodiments, at least one R₄ is N(R₆′)₂, and the twoR₆′ together with the atoms to which they are attached form azetidinyl,piperidinyl, morpholinyl, or thiomorpholino, each of which is optionallysubstituted with one or more R₉.

(H2e-10) In some embodiments, at least one R₄ is N(R₆′)₂, and one of R₆′is C₁-C₆ alkyl or C₁-C₆ haloalkyl, as described herein, and the otherR₆′ is cycloalkyl, heterocyclyl comprising one or two 3- to 7-memberedrings and 1-3 heteroatoms selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S, as described herein, wherein thecycloalkyl, heterocyclyl, aryl, or heteroaryl moiety is optionallysubstituted with one or more R₉.

(H2f) In some embodiments, at least one R₄ is C₆-C₁₀ aryl (e.g., phenyl)or heteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, isoquinolinyl, indolyl, pyrazolopyridinyl,indazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, orbenzotriazolyl), wherein the aryl or heteroaryl moiety is optionallysubstituted with one or more R₉.

(H2f-1) In some embodiments, at least one R₄ is C₆-C₁₀ aryl (e.g.,phenyl), wherein the aryl moiety is optionally substituted with one ormore R₉.

(H2f-2) In some embodiments, at least one R₄ is heteroaryl comprisingone or two 5- or 6-membered rings and 1-3 heteroatoms selected from N,O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,isothiazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,isoquinolinyl, indolyl, pyrazolopyridinyl, indazolyl, benzofuranyl,benzoxazolyl, benzothiazolyl, or benzotriazolyl), wherein the heteroarylmoiety is optionally substituted with one or more R₉. In someembodiments, at least one R₄ is heteroaryl comprising one 5- or6-membered ring and 1-3 heteroatoms selected from N, O, and S, asdescribed herein, wherein the heteroaryl moiety is optionallysubstituted with one or more R₉. In some embodiments, at least one R₄ isheteroaryl comprising one 5-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, as described herein, wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, atleast one R₄ is heteroaryl comprising one 6-membered ring and 1-3heteroatoms selected from N, O, and S, as described herein, wherein theheteroaryl moiety is optionally substituted with one or more R₉.

(H3) In some embodiments, only one R₄ is halogen, CN, OH, N(R₆′)₂, C₁-C₆alkoxy, C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, Q-T, C₆-C₁₀ aryl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl moiety isoptionally substituted with one or more R₉.

(H3a) In some embodiments, only one R₄ is halogen (e.g., F, Cl, Br, orI), CN, OH, N(R₆′)₂, C₁-C₆ alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy, pentoxy, or hexoxy), C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, or Q-T.

(H3b) In some embodiments, only one R₄ is CN, OH, N(R₆′)₂, C₁-C₆ alkoxy(e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy),C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, or Q-T.

(H3c) In some embodiments, only one R₄ is C(═O)N(R₆)₂, C(═O)OR₆,C(═O)R₆, or Q-T.

(H3d) In some embodiments, only one R₄ is Q-T.

(H3e) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ is H,and the other R₆′ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇), C₁-C₆ haloalkyl (e.g., methyl, ethyl,n-propyl, propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), or hexyl (straight or branched), each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I)), C₃-C₇cycloalkyl, heterocyclyl comprising one or two 3- to 7-membered ringsand 1-3 heteroatoms selected from N, O, and S (e.g., aziridinyl,oxiranyl, thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl, azetidinyl,oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolany, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl,azepanyl, oxepanyl, thiepanyl, diazepanyl, hexahydropyridazinyl,hexahydropyrimidinyl, tetrahydrothiopyranyl, or thiomorpholinyl), C₆-C₁₀aryl (e.g., phenyl), or heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the cycloalkyl,heterocyclyl, aryl, or heteroaryl moiety is optionally substituted withone or more R₉.

(H3e-1) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇), or C₁-C₆ haloalkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl(straight or branched), or hexyl (straight or branched), each of whichis substituted with one or more halogen (e.g., F, Cl, Br, or I)).

(H3e-2) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is optionallysubstituted with one or more R₇).

(H3e-3) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is C₁-C₆ haloalkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is substitutedwith one or more halogen (e.g., F, Cl, Br, or I)).

(H3e-4) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is C₃-C₇ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, or cycloheptyl), wherein the cycloalkyl moietyis optionally substituted with one or more R₉.

(H3e-5) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is heterocyclyl comprising one or two 3- to7-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,aziridinyl, oxiranyl, thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl,azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,isothiazolidinyl, dioxolanyl, dithiolany, piperidinyl,tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl,dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl,azepanyl, oxepanyl, thiepanyl, diazepanyl, hexahydropyridazinyl,hexahydropyrimidinyl, tetrahydrothiopyranyl, or thiomorpholinyl),wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is heterocyclyl comprising one 4- to 6-memberedring and 1-3 heteroatoms selected from N, O, and S, as described herein,wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is heterocyclyl comprising one 4- to 5-memberedring and 1-3 heteroatoms selected from N, O, and S, as described herein,wherein the heterocyclyl moiety is optionally substituted with one ormore R₉. In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is heterocyclyl comprising one 4-membered ring and1-2 heteroatoms selected from N, O, and S, as described herein, whereinthe heterocyclyl moiety is optionally substituted with one or more R₉.In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ is H, andthe other R₆′ is heterocyclyl comprising one 4-membered ring and 1heteroatom selected from N, O, and S, as described herein, wherein theheterocyclyl moiety is optionally substituted with one or more R₉.

(H3e-6) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is C₆-C₁₀ aryl (e.g., phenyl), wherein the arylmoiety is optionally substituted with one or more R₉.

(H3e-7) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isH, and the other R₆′ is heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, onlyone R₄ is N(R₆′)₂, and one of R₆′ is H, and the other R₆′ is heteroarylcomprising one 5- or 6-membered ring and 1-3 heteroatoms selected fromN, O, and S, as described herein, wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, onlyone R₄ is N(R₆′)₂, and one of R₆′ is H, and the other R₆′ is heteroarylcomprising one 5-membered ring and 1-3 heteroatoms selected from N, O,and S, as described herein, wherein the heteroaryl moiety is optionallysubstituted with one or more R₉. In some embodiments, only one R₄ isN(R₆′)₂, and one of R₆′ is H, and the other R₆′ is heteroaryl comprisingone 6-membered ring and 1-3 heteroatoms selected from N, O, and S, asdescribed herein, wherein the heteroaryl moiety is optionallysubstituted with one or more R₉.

(H3e-8) In some embodiments, only one R₄ is N(R₆′)₂, and the two R₆′ areeach independently C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight or branched), orhexyl (straight or branched), each of which is optionally substitutedwith one or more R₇), or C₁-C₆ haloalkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched), each of which is substitutedwith one or more halogen (e.g., F, Cl, Br, or I)).

(H3e-9) In some embodiments, only one R₄ is N(R₆′)₂, and the two R₆′together with the atoms to which they are attached form a 3- to10-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O,and S (e.g., aziridinyl, oxiranyl, thiiranyl, diaziridinyl,oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl,dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolany,piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl,thiomorpholinyl, dioxanyl, dithianyl, hexahydro-1,3,5-triazinyl,trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, diazepanyl,hexahydropyridazinyl, hexahydropyrimidinyl, tetrahydrothiopyranyl, orthiomorpholinyl), wherein the heterocyclyl is optionally substitutedwith one or more R₉. In some embodiments, only one R₄ is N(R₆′)₂, andthe two R₆′ together with the atoms to which they are attached form a 3-to 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N,O, and S, as described herein, and is optionally substituted with one ormore R₉. In some embodiments, only one R₄ is N(R₆′)₂, and the two R₆′together with the atoms to which they are attached form a 4- to6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O,and S, as described herein, and is optionally substituted with one ormore R₉. In some embodiments, only one R₄ is N(R₆′)₂, and the two R₆′together with the atoms to which they are attached form azetidinyl,piperidinyl, morpholinyl, or thiomorpholino, each of which is optionallysubstituted with one or more R₉.

(H3e-10) In some embodiments, only one R₄ is N(R₆′)₂, and one of R₆′ isC₁-C₆ alkyl or C₁-C₆ haloalkyl, as described herein, and the other R₆′is cycloalkyl, heterocyclyl comprising one or two 3- to 7-membered ringsand 1-3 heteroatoms selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S, as described herein, wherein thecycloalkyl, heterocyclyl, aryl, or heteroaryl moiety is optionallysubstituted with one or more R₉.

(H3f) In some embodiments, only one R₄ is C₆-C₁₀ aryl (e.g., phenyl) orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, isoquinolinyl, indolyl, pyrazolopyridinyl,indazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, orbenzotriazolyl), wherein the aryl or heteroaryl moiety is optionallysubstituted with one or more R₉.

(H3f-1) In some embodiments, only one R₄ is C₆-C₁₀ aryl (e.g., phenyl),wherein the aryl moiety is optionally substituted with one or more R₉.

(H3f-2) In some embodiments, only one R₄ is heteroaryl comprising one ortwo 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S(e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, onlyone R₄ is heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, as described herein, wherein theheteroaryl moiety is optionally substituted with one or more R₉. In someembodiments, only one R₄ is heteroaryl comprising one 5-membered ringand 1-3 heteroatoms selected from N, O, and S, as described herein,wherein the heteroaryl moiety is optionally substituted with one or moreR₉. In some embodiments, only one R₄ is heteroaryl comprising one6-membered ring and 1-3 heteroatoms selected from N, O, and S, asdescribed herein, wherein the heteroaryl moiety is optionallysubstituted with one or more R₉.

(H3g) In some embodiments, at least one R₄ is C₁-C₆ alkoxy (e.g.,methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy).

(H3g-1) In some embodiments, only one R₄ is C₁-C₆ alkoxy (e.g., methoxy,ethoxy, propoxy, butoxy, pentoxy, or hexoxy).

(I1) In some embodiments, at least one Q is C₁-C₄ alkylene (e.g.,methylene, ethylene, propylene, or butylene).

(I2) In some embodiments, at least one Q is O—(C₁-C₄) alkylene (e.g.,O-methylene, O-ethylene, O-propylene, or O-butylene).

(J1) In some embodiments, at least one T is C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, or butoxy), OH, N(R₆)₂, N(R₅)C(═O)R₆, N(R₅)C(═O)OR₆,C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, C₆-C₁₀ aryl, or heteroaryl comprisingone or two 5- or 6-membered rings and 1-3 heteroatoms selected from N,O, and S, wherein the aryl or heteroaryl moiety is optionallysubstituted with one or more R₉.

(J2) In some embodiments, at least one T is C₁-C₄ alkoxy (e.g., methoxy,ethoxy, propoxy, or butoxy).

(J3) In some embodiments, at least one T is NH₂, NH(R₆), or N(R₆)₂.

(J3-1) In some embodiments, at least one T is NH₂, NH(R₆), or N(R₆)₂,wherein R₆ is C₁-C₄ alkyl moiety is selected from methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl.

(J4) In some embodiments, at least one T is N(R₅)C(═O)R₆ orN(R₅)C(═O)OR₆.

(J5) In some embodiments, at least one T is C(═O)N(R₆)₂, C(═O)OR₆, orC(═O)R₆.

(J6) In some embodiments, at least one T is OH.

(J7) In some embodiments, at least one T is C₆-C₁₀ aryl or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl moiety isoptionally substituted with one or more R₉.

(J7-1) In some embodiments, at least one T is C₆-C₁₀ aryl (e.g.,phenyl), optionally substituted with one or more R₉.

(J7-2) In some embodiments, at least one T is heteroaryl comprising oneor two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O,and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), optionally substituted with one ormore R₉. In some embodiments, at least one T is heteroaryl comprisingone 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S,as described herein, wherein the heteroaryl moiety is optionallysubstituted with one or more R₉. In some embodiments, at least one T isheteroaryl comprising one 5-membered ring and 1-3 heteroatoms selectedfrom N, O, and S, as described herein, wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, atleast one T is heteroaryl comprising one 6-membered ring and 1-3heteroatoms selected from N, O, and S, as described herein, wherein theheteroaryl moiety is optionally substituted with one or more R₉.

(K1) In some embodiments, each R₅ is H.

(K2) In some embodiments, at least one R₅ is C₁-C₄ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

(L1) In some embodiments, each R₆ is H.

(L2) In some embodiments, at least one R₆ is C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl(straight or branched), or hexyl (straight or branched), each of whichis optionally substituted with one or more R₇), C₁-C₆ haloalkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,pentyl (straight or branched), or hexyl (straight or branched), each ofwhich is substituted with one or more halogen (e.g., F, Cl, Br, or I)),C₆-C₁₀ aryl (e.g., phenyl), or heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S (e.g.,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the aryl or heteroarylmoiety is optionally substituted with one or more R₉.

(L2a) In some embodiments, at least one R₆ is C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl(straight or branched), or hexyl (straight or branched), each of whichis optionally substituted with one or more R₇), or C₁-C₆ haloalkyl(e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, pentyl (straight or branched), or hexyl (straight or branched),each of which is substituted with one or more halogen (e.g., F, Cl, Br,or I)).

(L2b) In some embodiments, at least one R₆ is C₁-C₆ alkyl (e.g., methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl(straight or branched), or hexyl (straight or branched), each of whichis optionally substituted with one or more R₇).

(L2c) In some embodiments, at least one R₆ is C₆-C₁₀ aryl (e.g.,phenyl), wherein the aryl moiety is optionally substituted with one ormore R₉.

(L2d) In some embodiments, at least one R₆ is heteroaryl comprising oneor two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O,and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl,pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, isoquinolinyl, indolyl,pyrazolopyridinyl, indazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, or benzotriazolyl), wherein the heteroaryl moiety isoptionally substituted with one or more R₉. In some embodiments, atleast one R₆ is heteroaryl comprising one 5- or 6-membered ring and 1-3heteroatoms selected from N, O, and S, as described herein, wherein theheteroaryl moiety is optionally substituted with one or more R₉. In someembodiments, at least one R₆ is heteroaryl comprising one 5-memberedring and 1-3 heteroatoms selected from N, O, and S, as described herein,wherein the heteroaryl moiety is optionally substituted with one or moreR₉. In some embodiments, at least one R₆ is heteroaryl comprising one6-membered ring and 1-3 heteroatoms selected from N, O, and S, asdescribed herein, wherein the heteroaryl moiety is optionallysubstituted with one or more R₉.

(L2e) In some embodiments, two R₆ together with the atoms to which theyare attached form a 3- to 10-membered heterocyclyl comprising 1-3heteroatoms selected from N, O, and S (e.g., aziridinyl, oxiranyl,thiiranyl, diaziridinyl, oxaziridinyl, dioxiranyl, azetidinyl, oxetanyl,thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,dioxolanyl, dithiolany, piperidinyl, tetrahydropyranyl, thianyl,piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl,hexahydro-1,3,5-triazinyl, trioxanyl, trithianyl, azepanyl, oxepanyl,thiepanyl, diazepanyl, hexahydropyridazinyl, hexahydropyrimidinyl,tetrahydrothiopyranyl, or thiomorpholinyl), wherein the heterocyclyl isoptionally substituted with one or more R₉. In some embodiments, two R₆together with the atoms to which they are attached form a 3- to6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O,and S, as described herein, and is optionally substituted with one ormore R₉. In some embodiments, two R₆ together with the atoms to whichthey are attached form a 4- to 6-membered heterocyclyl comprising 1-3heteroatoms selected from N, O, and S, as described herein, and isoptionally substituted with one or more R₉.

(M1a) In some embodiments, each R₇ is independently N(R₈)₂, and each R₈is H.

(M1b) In some embodiments, each R₇ is independently N(R₈)₂, and one R₈is H, and the other R₈ is C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight orbranched), or hexyl (straight or branched)).

(M1c) In some embodiments, each R₇ is independently N(R₈)₂, and each R₈is independently C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight or branched), orhexyl (straight or branched)).

(M2a) In some embodiments, each R₇ is independently OR₈, and R₈ is H.

(M2b) In some embodiments, each R₇ is independently OR₈, and R₈ is C₁-C₆alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, pentyl (straight or branched), or hexyl (straight orbranched)).

(M2c) In some embodiments, each R₇ is independently C₆-C₁₀ aryl (e.g.,phenyl) or heteroaryl comprising one or two 5- or 6-membered rings and1-3 heteroatoms selected from N, O, and S (e.g., pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, isoquinolinyl, indolyl, pyrazolopyridinyl,indazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, orbenzotriazolyl).

(M2c-1) In some embodiments, each R₇ is independently C₆-C₁₀ aryl (e.g.,phenyl).

(M2c-2) In some embodiments, each R₇ is independently heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S (e.g., pyridinyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, thiophenyl,furanyl, isoquinolinyl, indolyl, pyrazolopyridinyl, indazolyl,benzofuranyl, benzoxazolyl, benzothiazolyl, or benzotriazolyl).

(N1) In some embodiments, each R₉ is independently oxo, halogen (e.g.,F, Cl, Br, or I), OH, CN, NH₂, N(C₁-C₄ alkyl)₂ (e.g., dimethylamino,methylethylamino, diethylamino, methylpropylamino, ethylpropylamino,dipropylamino, methylbutylamino, ethylbutylamino, propylbutylamino, ordibutyamino), C₁-C₆ alkyl (e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straight or branched), orhexyl (straight or branched)), C₁-C₆ haloalkyl (e.g., methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl (straightor branched), or hexyl (straight or branched), each of which issubstituted with one or more halogen (e.g., F, Cl, Br, or I)), C₁-C₆alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexyloxy),or C₁-C₆ haloalkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, orhexyloxy, each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I)), wherein the C₁-C₆ alkyl is optionally substitutedwith one or more groups selected from oxo, OH, O(C₁-C₄ alkyl), CN, NH₂,and N(C₁-C₄ alkyl)₂ (e.g., dimethylamino, methylethylamino,diethylamino, methylpropylamino, ethylpropylamino, dipropylamino,methylbutylamino, ethylbutylamino, propylbutylamino, or dibutyamino).

(N2) In some embodiments, each R₉ is independently OH, CN, NH₂, N(C₁-C₄alkyl)₂ (e.g., dimethylamino, methylethylamino, diethylamino,methylpropylamino, ethylpropylamino, dipropylamino, methylbutylamino,ethylbutylamino, propylbutylamino, or dibutyamino), C₁-C₆ alkyl (e.g.,methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,pentyl (straight or branched), or hexyl (straight or branched)), C₁-C₆haloalkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl, t-butyl, pentyl (straight or branched), or hexyl (straight orbranched), each of which is substituted with one or more halogen (e.g.,F, Cl, Br, or I)), C₁-C₆ alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy,pentoxy, or hexyloxy), or C₁-C₆ haloalkoxy (e.g., methoxy, ethoxy,propoxy, butoxy, pentoxy, or hexyloxy, each of which is substituted withone or more halogen (e.g., F, Cl, Br, or I)), wherein the C₁-C₆ alkyl isoptionally substituted with one or more groups selected from OH, CN,NH₂, and N(C₁-C₄ alkyl)₂ (e.g., dimethylamino, methylethylamino,diethylamino, methylpropylamino, ethylpropylamino, dipropylamino,methylbutylamino, ethylbutylamino, propylbutylamino, or dibutyamino).

For a compound of any of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, IIa,IIb, IIc, IId, IIe, IIf, or IIg, where applicable, each of thesubstituent groups illustrated herein for any of Cy, X₁, X₂, A₁, A₂, A₃,A₄, R₁, R₂, R₃, R₄, R₅, R₆, R₆′, R₇, R₈, R₉, Q, and T, can be combinedwith any of the substituent groups illustrated herein for one or more ofthe remainder of Cy, X₁, X₂, A₁, A₂, A₃, A₄, R₁, R₂, R₃, R₄, R₅, R₆,R₆′, R₇, R₈, R₉, Q, and T.

For example:

(O1) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and the Cy ring is as illustratedin (B1).

(O2) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and the Cy ring is as illustratedin (B2).

(O3) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and the Cy ring is as illustratedin (B3).

(P1) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in (G1).

(P2) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in (G2).

(P3) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in any of (G3)-(G3d).

(P4) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in any of (G4)-(G4f).

(P5) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in any of (G5)-(G5d).

(P6) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in any of (G6).

(P7) The thiazolyl ring

is as illustrated in any of (A1)-(A3), and A₁, A₂, A₃, and A₄ are eachas illustrated in any of (G7).

(Q1a) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in (G1).

(Q1b) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in (G2).

(Q1c) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G3)-(G3d).

(Q1d) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G4)-(G4f).

(Q1e) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G5)-(G5d).

(Q1f) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G6).

(Q1g) The Cy ring is as illustrated in (B1), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G7).

(Q2a) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in (G1).

(Q2b) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in (G2).

(Q2c) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G3)-(G3d).

(Q2d) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G4)-(G4f).

(Q2e) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G5)-(G5d).

(Q2f) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G6).

(Q2g) The Cy ring is as illustrated in (B2), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G7).

(Q3a) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in (G1).

(Q3b) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in (G2).

(Q3c) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G3)-(G3d).

(Q3d) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G4)-(G4f).

(Q3e) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G5)-(G5d).

(Q3f) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G6).

(Q3g) The Cy ring is as illustrated in (B3), and A₁, A₂, A₃, and A₄ areeach as illustrated in any of (G7).

(Q4a) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in (G1).

(Q4b) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in (G2).

(Q4c) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in any of (G3)-(G3d).

(Q4d) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in any of (G4)-(G4f).

(Q4e) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in any of (G5)-(G5d).

(Q4f) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in any of (G6).

(Q4g) The thiazolyl ring

and the Cy ring are illustrated as in any of (O1)-(O3), and A₁, A₂, A₃,and A₄ are each as illustrated in any of (G7).

(R1) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H1).

(R2) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H2).

(R3) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H2a).

(R₄) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H2b).

(R5) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H2c).

(R₆) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H2d).

(R7) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in any of (H2e)-(H2e-10).

(R8) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H2f)-(H2f-2).

(R9) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3).

(R10) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3a).

(R11) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3b).

(R12) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3c).

(R13) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3d).

(R14) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in any of (H3e)-(H3e-10).

(R15) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3f-1)-(H3f-2).

(R16) The thiazolyl ring

the Cy ring, and/or A₁, A₂, A₃, and A₄ are each as illustrated, asapplicable, in any or (A1)-(A3), (B1)-(B3), (G1)-(G7), and (O1)-(Q4g),R₄ is as illustrated in (H3g)-(H3g-1).

Non-limiting illustrative compounds of the application are listed inTable 1.

TABLE 1 Cmpd No. Structure Chemical Name 1

isopropyl (trans-4-(5-(4- (aminomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 2

isopropyl (trans-4-(5-(4- (acetamidomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 3

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 4

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4- yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 5

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(pyridin-3-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 6

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(1H-pyrazol-3-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 7

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(6-hydroxy-pyridin-3-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 8

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2,4- dimethoxypyrimidin-5- yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 9

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2H-indazol-6-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 10

isopropyl (trans-4-(5-(4-(2- aminopyrimidin-5-yl)-2-(N-(tert-butyl)sulfamoyl) phenyl)thiazol- 2-yl)cyclohexyl)carbamate 11

isopropyl (trans-4-(5-(4- (benzofuran-5-yl)-2-(N-(tert- butyl)sulfamoyl)phenyl)thiazol- 2-yl)cyclohexyl)carbamate 12

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(pyrimidin-5-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 13

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(3,6-dimethoxypyridazin-4- yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 14

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2-methylthiazol-5- yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 15

isopropyl (trans-4-(5-(4- (benzo[d]thiazol-6-yl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 16

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(5-((dimethylamino)methyl)pyridin- 3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 17

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(5-methyl-1H-pyrazol-4-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 18

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(6-cyano-pyridin-3-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 19

isopropyl (trans-4-(5-(4-(1H- benzo[d][1,2,3]triazol-6-yl)-2-(N- (tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 20

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(6-(hydroxymethyl)pyridin-3- yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate21

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(3-methyl-1H-indol-6-yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 22

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2-(trifluoromethyl)pyridin-4- yl)phenyl)thiazol-2- yl)cyclohexyl)carbamate23

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-hydroxy-phenyl)thiazol-2- yl)cyclohexyl)carbamate 24

isopropyl (trans-4-(5-(4-hydroxy- 2-sulfamoylphenyl)thiazol-2-yl)cyclohexyl)carbamate 25

isopropyl N-[trans-4-[5-[4-[2- (tert- butoxycarbonylamino)ethoxy]-2-(tert- butylsulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 26

isopropyl (trans-4-(5-(4-(2- aminoethoxy)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 27

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-isopropoxy-phenyl)thiazol-2- yl)cyclohexyl)carbamate 28

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-methoxy-phenyl)thiazol-2- yl)cyclohexyl)carbamate 29

tert-butyl (2-(3-(N-(tert- butyl)sulfamoyl)-4-(2-(trans-4- ((iso-propoxycarbonyl)amino) cyclohexyl)thiazol-5- yl)phenoxy)ethyl)methyl)carbamate 30

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2-(dimethyl-amino)ethoxy)phenyl)thiazol-2- yl)cyclohexyl)carbamate 31

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2-methoxy-ethoxy)phenyl)thiazol-2- yl)ycclohexyl)carbamate 32

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2-(methyl-amino)ethoxy)phenyl)thiazol-2- yl)cyclohexyl)carbamate 33

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(isobutoxymethyl)phenyl)thiazol- 2-yl)cyclohexyl)carbamate 34

oxetan-3-yl (trans-4-(5-(2-(N- (tert-butyl)sulfamoyl)-4-isobutoxymethyl)phenyl)thiazol- 2-yl)cyclohexyl)carbamate 35

isopropyl (trans-4-(5-(4- (dimethylamino)-2-(N-ethylsulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 36

isopropyl (trans-4-(5-(4-cyano-2- (N-ethylsulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 37

isopropyl (trans-4-(5-(3-(N- ethylsulfamoyl)pyridin-4- yl)thiazol-2-yl)cyclohexyl)carbamate 38

isopropyl (trans-4-(5-(4-((1H- imidazol-2-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 39

oxetan-3-yl (trans-4-(5-(4-((1H- imidazol-2-yl)amino)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 40

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(2-(isopropylamino)-2- oxoethyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate41

oxetan-3-yl (trans-4-(5-(2-(N- (tert-butyl)sulfamoyl)-4-(2-(isopropylamino)-2- oxoethyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate42

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2- yl)cyclohexyl)carbamate 43

oxetan-3-yl (trans-4-(5-(2-(N- (tert-butyl)sulfamoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2- yl)cyclohexyl)carbamate 44

isopropyl (trans-4-(5-(2- sulfamoylphenyl)thiazol-2-yl)cyclohexyl)carbamate 45

isopropyl (trans-4-(5-(2-(N- ethylsulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 46

isopropyl (trans-4-(5-(2-(N-(tert- butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 47

isopropyl (trans-4-(5-(2-(azetidin- 1-ylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 48

3-(N-ethylsulfamoyl)-4-(2-(trans- 4- ((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)benzoic acid 49

isopropyl (trans-4-(5-(4- carbamoyl-2-(N-ethylsulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 50

isopropyl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(isopropylcarbamoyl)phenyl) thiazol-2-yl)cyclohexyl)carbamate 51

isopropyl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(isobutoxymethyl)phenyl)thiazol- 2-yl)cyclohexyl)carbamate 52

oxetan-3-yl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-isobutoxymethyl)phenyl)thiazol- 2-yl)cyclohexyl)carbamate 53

isopropyl (trans-4-(5-(2-(azetidin- 1-ylsulfonyl)-4-(dimethylamino)phenyl)thiazol-2- yl)cyclohexyl)carbamate 54

isopropyl (trans-4-(5-(2-(azetidin- 1-ylsulfonyl)-4-cyanophenyl)thiazol-2- yl)cyclohexyl)carbamate 55

isopropyl (trans-4-(5-(3-(azetidin- 1-ylsulfonyl)pyridin-4-yl)thiazol-2-yl)cyclohexyl)carbamate 56

isopropyl (trans-4-(5-(4-((1H- imidazol-2-yl)amino)-2-(N-ethylsulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 57

oxetan-3-yl (trans-4-(5-(4-((1H- imidazol-2-yl)amino)-2-(N-ethylsulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 58

isopropyl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(2- (isopropylamino)-2-oxoethyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 59

oxetan-3-yl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(2- (isopropylamino)-2-oxoethyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 60

isopropyl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2- yl)cyclohexyl)carbamate 61

oxetan-3-yl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2- yl)cyclohexyl)carbamate 62

oxetan-3-yl (trans-4-(5-(2- sulfamoylphenyl)thiazol-2-yl)cyclohexyl)carbamate 63

oxetan-3-yl (trans-4-(4-(2-(N- ethylsulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 64

oxetan-3-yl (trans-4-(5-(2-(N- (tert- butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 65

oxetan-3-yl (trans-4-(5-(2- (azetidin-1- ylsulfonyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate 66

3-(N-ethylsulfamoyl)-4-(2-(trans- 4-(((oxetan-3-yloxy)carbonyl)amino)cyclohexyl) thiazol-5-yl)benzoic acid 67

oxetan-3-yl (trans-4-(5-(4- carbamoyl-2-(N-ethylsulfamoyl)phenyl)thiazol-2- yl)cyclohexyl)carbamate 68

oxetan-3-yl (trans-4-(5-(2-(N- ethylsulfamoyl)-4-(isopropylcarbamoyl)phenyl) thiazol-2-yl)cyclohexyl)carbamate 69

isopropyl (trans-N-(4-(5-(2- (ethylsulfamoyl)-4-((3-isopropyl- oxetan-3-yl)amino)phenyl)thiazol-2- yl)cyclohexyl))carbamate 70

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(3- isobutyloxetan-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 71

methyl trans-3- (ethylsulfamoyl)-4-[2-[4- (isopropoxycarbonyl-amino)cyclohexyl]thiazol-5- yl]benzoate 72

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(hydroxy-methyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 73

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1H- imidazol-2-ylamino)methyl]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 74

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(oxazol-2- ylamino)methyl]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 75

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(1H-imidazol-2-yl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 76

methyl trans-2-[3- (ethylsulfamoyl)-4-[2-[4- (isopropoxycarbonylamino)cyclohexyl]thiazol-5- yl]phenyl]acetate 77

trans-2-[3-(ethylsulfamoyl)-4-[2- [4-(isopropoxycarbonyl-amino)cyclohexyl]thiazol-5- yl]phenyl]acetic acid 78

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(1H- imidazol-2-ylmethyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 79

isopropyl trans-N-[4-[5-[4-[2- (benzylamino)-2-oxo-ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 80

isopropyl trans-N-[4-[5-[4-[2- (isopropyl(methyl)amino)-2-oxo-ethyl]-2-(ethyl- sulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 81

isopropyl trans-N-[4-[5-[4-[2- (benzyl(methyl)amino)-2-oxo-ethyl]-2-(ethyl- sulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 82

isopropyl trans-N-[4-[5-[4-[2- oxo-2-(pyrrolidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 83

isopropyl trans-N-[4-[5-[4-[2- oxo-2-(piperidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 84

isopropyl trans-N-[4-[5-[4-[2- oxo-2-(morpholin-4-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 85

isopropyl trans-N-[4-[5-[4-[2- oxo-2-(3-hydroxyazetidin-1-yl)ethyl]-2-(ethyl- sulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate86

isopropyl trans-N-[4-[5-[4-[2- amino-2-oxo-ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 87

isopropyl trans-N-[4-[5-[4-[2- oxo-2-(azetidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 88

isopropyl trans-N-[4-[5-(4- amino-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2- yl]cyclohexyl]carbamate 89

isopropyl trans-N-[4-[5-(4- (methylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2- yl]cyclohexyl]carbamate 90

isopropyl trans-N-[4-[5-[4-(1H- imidazol-2-ylamino)-2-sulfamoyl-phenyl]thiazol-2- yl]cyclohexyl]carbamate 91

isopropyl trans-N-[4-[5-[2- (dimethylsulfamoyl)-4-(1H- imidazol-2-ylamino)phenyl]thiaol-2- yl]cyclohexyl]carbamate 92

isopropyl trans-N-[4-[5-[4-(1H- imidazol-2-ylamino)-2-pyrrolidin-1-ylsulfonyl- phenyl]thiaol-2- yl]cyclohexyl]carbamate 93

isopropyl trans-N-[4-[5-(2- methylsulfamoylphenyl)thiazol-2-yl]cyclohexyl]carbamate 94

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(1H- imidazol-2-ylcarbamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 95

isopropyl trans-N-[4-[5-[4- pyrrolidin-1-ylcarbonyl-2-(ethylsulfamoyl)phenyl] thiazol- 2-yl]cyclohexyl]carbamate 96

oxetan-3-yl 4-(5-(2-(N- ethylsulfamoyl)-4-(2- (isopropylamino)-2-oxoethyl)phenyl)thiazol-2- yl)piperazine-1-carboxylate 97

isopropyl trans-N-[4-[5-[4-[2- (benzylamino)-2-oxo-ethyl]-2- (tert-butylsulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 98

oxetan-3-yl trans-N-[4-[5-[4-[2- (benzylamino)-2-oxo-ethyl]-2- (tert-butylsulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 99

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2- yl]cyclohexyl]carbamate 100

oxetan-3-yl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2- yl]cyclohexyl]carbamate 101

isopropyl trans-N-[4-[5-[2-(tert- butylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2- yl]cyclohexyl]carbamate 102

oxetan-3-yl trans-N-[4-[5-[2- (tert-butylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2- yl]cyclohexyl]carbamate 103

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(oxazol-2-ylmethyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 104

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-oxazol-2-yl-phenyl]thiazol-2- yl]cyclohexyl]carbamate 105

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1- methylimidazol-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 106

isopropyl cis-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1- methylimidazol-2-yl)amino]phenyl] thiazol-2- yl]cyclohexyl]carbamate 107

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1-isobutyl- imidazol-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 108

cyclopropyl trans-N-[4-[5-[4- amino-2-(ethylsulfamoyl) phenyl]thiazol-2-yl]cyclohexyl]carbamate 109

cyclopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(1H- imidazol-2-ylamino)phenyl]thiazol-2- yl]cyclohexyl]carbamate 110

isopropyl cis-N-[4-[5-[2-(tert- butylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2- yl]cyclohexyl]carbamate 111

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(4-isopropyl-2-pyridyl)amino]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 112

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(6-isopropyl-2-pyridyl)amino]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 113

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5-isopropyl-2-pyridyl)amino]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 114

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[3- isopropoxyazetidin-1-yl]phenyl]thiazol-2- yl]cyclohexyl]carbamate 115

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5-isopropyl-1,3,4-thiadiazol-2- y)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate116

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(3- methyloxetan-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 117

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[methyl(1-methyl-1H-imidazol-2- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate118

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1,3,4- oxadiazool-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 119

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1,3,4- thiadiazol-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 120

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1H-pyrazol-4-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 121

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1H-pyrazol-5-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 122

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyrazin-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 123

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyridazin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 124

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyrimidin-4-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 125

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyridin-4-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 126

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyridin-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 127

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyrimidin-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 128

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(pyridin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 129

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1-isopropyl-1H-pyrazol-5- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 130

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[4- hydroxypiperidin-1-yl]phenyl]thiazol-2- yl]cyclohexyl]carbamate 131

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(2- hydroxyethyl)(methyl))amino]phenyl]thiaol- 2-yl]cyclohexyl]carbamate 132

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(2- methoxyethyl)(methyl))amino]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 133

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[1,1-dioxidothiomorpholino]phenyl] thiazol-2-yl]cyclohexyl] carbamate 134

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[morpholino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 135

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[piperidin-1-yl]phenyl]thiazol-2- yl]cyclohexyl]carbamate 136

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(2-isopropylpyrimidin-4- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate137

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(oxetan-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 138

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(3- isopropylimidazol-4-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 139

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1-isopropyl-1H-imidazol-4- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 140

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(6- isopropylpyrazin-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 141

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5-methyl-1H-imidazol-2- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 142

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5-isopropyl-1H-imidazol-2- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 143

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(6-isopropylpyridazin-3- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate144

isopropyl trans-N-[4-[5-[4- (azetidin-3-ylamino)-2-(ethyl-sulfamoyl)phenyl]thiazol-2- yl]cyclohexyl]carbamate 145

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1-isobutyl- azetidin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 146

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[[1-(2-methylpropanoyl)azetidin-3- yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate 147

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(3- methylazetidin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 148

isopropyl trans-N-[4-[5-[2- (azetidin-1-ylsulfonyl)-4-(1H- imidazol-2-ylamino)phenyl]thiazol-2- yl]cyclohexyl]carbamate 149

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(2H-triazol-4-ylamino)phenyl]thiazol-2- yl]cyclohexyl]carbamate 150

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[1H- imidazol-2-yl(methyl)amino]phenyl]thiazol- 2-yl]cyclohexyl]carbamate 151

isopropyl trans-N-[4-[5-[2-(tert- butylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 152

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-(4H-1,2,4-triazl-3-ylamino)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 153

isopropyl trans-[4-[5-[4-(oxazol- 2-ylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl]thiazol-2- yl]cyclohexyl]carbamate 154

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4[(1- isopropylimidazol-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 155

isopropyl trans-N-[4-[5-[4-[(2- chloropyrimidin-4-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 156

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(2- hydroxypyrimidin-4-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 157

isopropyl trans-N-[4-[5-[4-[(6- ethylpyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 158

isopropyl trans-N-[4-[5-[4-[(5- ethylpyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 159

isopropyl trans-N-[4-[5-[4-[(6- chloropyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol- 2-yl]cyclohexyl]carbamate 160

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(6-oxo-1H- pyridazin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 161

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5- methylpyridazin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 162

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(6- methylpyridazin-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 163

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5- isopropylpyrazin-2-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 164

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(5-isopropylpyridazin-3- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate165

methyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(3- methyloxetan-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 166

methyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1H-pyrazol-4-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 167

methyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1H-pyrazol-5-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 168

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[[(3R)-1-isobutyl-2-oxo-azetidin-3- yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate 169

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[[(3S)-1-isobutyl-2-oxo-azetidin-3- yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate 170

tert-butyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(2- isopropylpyrazol-3-yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 171

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(6-isopropylpyrimidin-4- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate172

isopropyl trans-N-[4-[5-[2- (ethylsulfamoyl)-4-[(1-methyl-6-oxo-pyridazin-3- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate 173

isopropyl trans-N-[4-[5-[2-(tert- butylsulfamoyl)-4-[(6-chloropyridazin-3- yl)amino]phenyl]thiazol-2- yl]cyclohexyl]carbamate174

isopropyl trans-N-[4-[5-[2-(tert- butylsulfamoyl)-4-(pyridazin-3-ylamino)phenyl]thiazol-2- yl]cyclohexyl]carbamate

In some embodiments, a compound of the present application (e.g., acompound of any of the formulae or any individual compounds disclosedherein) is a pharmaceutically acceptable salt. In another embodiment, acompound of the present application (e.g., a compound of any of theformulae or any individual compounds disclosed herein) is a solvate. Inanother embodiment, a compound of the present application (e.g., acompound of any of the formulae or any individual compounds disclosedherein) is a hydrate.

The compounds of the present application may form salts which are alsowithin the scope of this application. Reference to a compound of theFormula herein is understood to include reference to salts thereof,unless otherwise indicated.

Representative “pharmaceutically acceptable salts” include, e.g.,water-soluble and water-insoluble salts, such as the acetate, amsonate(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium,calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate,dihydrochloride, edetate, edisylate, estolate, esylate, fumerate,fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate,hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts.

“Solvate” means solvent addition forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundsor salts have a tendency to trap a fixed molar ratio of solventmolecules in the crystalline solid state, thus forming a solvate. If thesolvent is water, the solvate formed is a hydrate; and if the solvent isalcohol, the solvate formed is an alcoholate. Hydrates are formed by thecombination of one or more molecules of water with one molecule of thesubstance in which the water retains its molecular state as H₂O.

Compounds having one or more chiral centers can exist in variousstereoisomeric forms. Stereoisomers are compounds that differ only intheir spatial arrangement. Stereoisomers include all diastereomeric,enantiomeric, and epimeric forms as well as racemates and mixturesthereof.

The term “geometric isomer” refers to cyclic compounds having at leasttwo substituents, wherein the two substituents are both on the same sideof the ring (cis) or wherein the substituents are each on opposite sidesof the ring (trans). When a disclosed compound is named or depicted bystructure without indicating stereochemistry, it is understood that thename or the structure encompasses one or more of the possiblestereoisomers, or geometric isomers, or a mixture of the encompassedstereoisomers or geometric isomers. When a geometric isomer is depictedby name or structure, it is to be understood that the named or depictedisomer exists to a greater degree than another isomer, that is that thegeometric isomeric purity of the named or depicted geometric isomer isgreater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9%pure by weight. Geometric isomeric purity is determined by dividing theweight of the named or depicted geometric isomer in the mixture by thetotal weight of all of the geometric isomers in the mixture.

“Chiral isomer” means a compound with at least one chiral center.Compounds with more than one chiral center may exist either as anindividual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, astereoisomer may be characterized by the absolute configuration (R or S)of that chiral center. Absolute configuration refers to the arrangementin space of the substituents attached to the chiral center. Thesubstituents attached to the chiral center under consideration areranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog.(Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahnet al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951(London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem.Educ. 1964, 41, 116).

In some embodiments of the application, the compounds of the applicationare diastereomers. In some embodiments, the compounds are the syndiastereomer. In other embodiments, the compounds are the antidiastereomer.

Racemic mixture means 50% of one enantiomer and 50% of is correspondingenantiomer. When a compound with one chiral center is named or depictedwithout indicating the stereochemistry of the chiral center, it isunderstood that the name or structure encompasses both possibleenantiomeric forms (e.g., both enantiomerically-pure,enantiomerically-enriched or racemic) of the compound. When a compoundwith two or more chiral centers is named or depicted without indicatingthe stereochemistry of the chiral centers, it is understood that thename or structure encompasses all possible diastereomeric forms (e.g.,diastereomerically pure, diastereomerically enriched and equimolarmixtures of one or more diastereomers (e.g., racemic mixtures) of thecompound.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or stereoisomers by well-known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers also can be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

When a compound is designated by a name or structure that indicates asingle enantiomer, unless indicated otherwise, the compound is at least60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as“enantiomerically pure”). Optical purity is the weight in the mixture ofthe named or depicted enantiomer divided by the total weight in themixture of both enantiomers.

When the stereochemistry of a disclosed compound is named or depicted bystructure, and the named or depicted structure encompasses more than onestereoisomer (e.g., as in a diastereomeric pair), it is to be understoodthat one of the encompassed stereoisomers or any mixture of theencompassed stereoisomers is included. It is to be further understoodthat the stereoisomeric purity of the named or depicted stereoisomers atleast 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomericpurity in this case is determined by dividing the total weight in themixture of the stereoisomers encompassed by the name or structure by thetotal weight in the mixture of all of the stereoisomers.

It is also possible that the compounds of the application may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the application. “Tautomer” is one of two or more structuralisomers that exist in equilibrium and is readily converted from oneisomeric form to another. This conversion results in the formalmigration of a hydrogen atom accompanied by a switch of adjacentconjugated double bonds. Tautomers exist as a mixture of a tautomericset in solution. In solid form, usually one tautomer predominates. Insolutions where tautomerization is possible, a chemical equilibrium ofthe tautomers will be reached. The exact ratio of the tautomers dependson several factors, including temperature, solvent and pH. The conceptof tautomers that are interconvertable by tautomerizations is calledtautomerism. Of the various types of tautomerism that are possible, twoare commonly observed. In keto-enol tautomerism a simultaneous shift ofelectrons and a hydrogen atom occurs. Ring-chain tautomerism arises as aresult of the aldehyde group (—CHO) in a sugar chain molecule reactingwith one of the hydroxy groups (—OH) in the same molecule to give it acyclic (ring-shaped) form as exhibited by glucose. Common tautomericpairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acidtautomerism in heterocyclic rings (e.g., in nucleobases such as guanine,thymine and cytosine), amine-enamine and enamine-imine.

The application also comprehends isotopically-labeled compounds, whichare identical to those recited in the each of the formulae describedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number most commonly found in nature. Examples of isotopes that canbe incorporated into compounds of the application include isotopes ofhydrogen, carbon, nitrogen, fluorine, such as ³H, ¹¹C, ¹⁴C, ²H and ¹⁸F.

Compounds of the application that contain the aforementioned isotopesand/or other isotopes of other atoms are within the scope of the presentapplication. Isotopically-labeled compounds of the present application,for example those into which radioactive isotopes such as ³H, ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areuseful for their ease of preparation and detectability. ¹¹C and ¹⁸Fisotopes are useful in PET (positron emission tomography). PET is usefulin brain imaging. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example, increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of the application,can generally be prepared by carrying out the procedures disclosed inthe Schemes and/or in the Examples described herein, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. In some embodiments, the compounds of the applicationare not isotopically labelled.

Methods for Preparing the Compounds

The compounds of the present application may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the scheme described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, N.Y. 1999). These groups are removedat a convenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art. The selection processes,as well as the reaction conditions and order of their execution, shallbe consistent with the preparation of the compounds of the presentapplication.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present application includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compound but the individual enantiomers and/ordiastereomers as well. When a compound is desired as a single enantiomeror diastereomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be affected by any suitable method known in the art. See, forexample, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes. The compounds of the present application can beprepared in a number of ways well known to those skilled in the art oforganic synthesis. By way of example, the compounds of the presentapplication can be synthesized using the methods described below,together with synthetic methods known in the art of synthetic organicchemistry, or variations thereon as appreciated by those skilled in theart. Preferred methods include but are not limited to those methodsdescribed below. The compounds of the present application (i.e., acompound of Formula I) can be synthesized by following the stepsoutlined in General Schemes and/or General Methods below. Startingmaterials are either commercially available or made by known proceduresin the reported literature or as illustrated.

A carboxylic acid I is converted to the amide II using HBTU and ammoniumchloride. The resulting amide is reacted with Lawesson's reagent in THFto provide the thioamide III. Cyclization with2-bromo-1,1-diethoxyethane under acidic conditions gives the thiazole IVwhich is then brominated using N-bromosuccinimide. The bromothiazole Vis then reacted under Suzuki coupling conditions with the boronate VI togive the Rad51 inhibitor VII or an intermediate which is furthertransformed using conventional chemistry protocols.

2,5-dibromothiazole (VIII) is reacted with a cycloalkylamine orheterocyclic amine (IX) in DMF to give the bromothiazole X. A Suzukicoupling with the boronate VI provides the Rad51 inhibitor XI or anintermediate which is further transformed using conventional chemistryprotocols.

The following General Methods further illustrate the preparation of thecompounds of the present application. Although certainreagents/materials and conditions are described in the General Methods,it is understood that equivalent reagents/materials and conditions mayalso be used.

General Method Reaction Name A Amide coupling reaction B Borateformation C Suzuki Reaction A D Suzuki Reaction B E Deprotection oftert-butylsulfonamide F Buchwald Reaction G Sulfamide formation HReductive amination I Deprotection of SEM group J Hydrolysis reaction KSubstitution Reaction L Sandmeyer reaction

To a solution of carboxylic acid (1.0 eq.) and DIEA (15.0 eq.) in DMFmay be added NH₄Cl (10.0 eq.) and HATU (1.3 eq.). The mixture may bestirred at 25° C. for 12 h, then poured into H₂O and extracted withEtOAc (3×). The combined organic layers may be washed with brine, driedover Na₂SO₄, filtered, and concentrated to yield the amide product.

A mixture of Boc-protected amine (1.0 eq.), B₂Pin₂ (3.0 eq.), KOAc (3.0eq.) and Pd(dppf)Cl₂.CH₂Cl₂ (0.1 eq.) in dioxane may be degassed andpurged with N₂ (3×) and stirred at 80° C. for 12 h. The reaction mixturemay be concentrated and the residue may be purified by prep-TLC (SiO₂,Petroleum ether/Ethyl acetate=3/1) to yield the borate product.

A mixture of borate (1.0 eq.), thiazole (1.2 eq.), Na₂CO₃ (3.0 eq.),Pd(PPh₃)₄ (0.1 eq.) and KF (3.0 eq.) in EtOH/H₂O/Tol. may be degassedand purged with N₂ (3×) and then stirred at 80° C. for 12 h. Thereaction mixture may be concentrated and the residue may be purified byprep-TLC (SiO₂, Petroleum ether/Ethyl acetate=2/1) to yield the SuzukiReaction A product.

A mixture of brominated thiazole moiety (1.0 eq.),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(1.2 eq.), KOAc (3.0 eq.) and Pd(AmPhos)Cl₂ (0.1 eq.) in 1:0.25 EtOH/H₂Omay be degassed and purged with N₂ (3×), and then stirred at 80° C. for12 h. The reaction mixture may be concentrated and the residue may bepurified by prep-HPLC (column: Welch Ultimate AQ-C18 150*30 mm*5 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 50%-80%, 12 min) to yield theSuzuki Reaction B product.

To a solution ofN-(3-isopropyloxetan-3-yl)-2-methyl-propane-2-sulfinamide (1 eq.) in DCMmay be added HCl/EtOAc (4 M, 4.4 eq.). The mixture may be stirred at 0°C. for 5 min, then the reaction mixture may be diluted with MTBE thenthe solid may be formed. The residue may be concentrated under reducedpressure to remove solvent at 0° C. Then the residue may be trituratedwith MTBE:Petroleum ether=1:1 and filtered, the filter cake may becollected to yield 3-isopropyloxetan-3-amine which may be used into thenext step without further purification.

A mixture of 3-isopropyloxetan-3-amine (2 eq.), brominated thiazolemoiety (1 eq.), K₂CO₃ (3 eq.) and BrettPhos Pd G3 (0.1 eq.) in t-BuOHmay be stirred at 110° C. for 12 h under Ar atmosphere. The reactionmixture may be concentrated under reduced pressure, then the residue maybe purified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=2:1) andpurified by prep-HPLC (column: YMC-Actus Triart C18 100*30 mm*5 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 25%-60%, 10 min) to yield theBuchwald Reaction product.

To a solution of TEA (3 eq.) in DCM may be added alkylamine (1.1 eq.) at−20° C. Then the methyl 4-bromo-3-chlorosulfonyl-benzoate (1.0 eq.) maybe added batchwise. The mixture may be stirred at −20° C. for 5 min,then the reaction mixture may be quenched with HCl (1M, pH=2) andextracted with DCM, the organic layers may be dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield the sulfamideformation product.

To a mixture of 1-(2-trimethylsilylethoxymethyl)imidazol-2-amine (1.5eq.) and formyl-phenyl-thiazol moiety (1 eq.) in DCM may be addedTi(i-PrO)₄ (2 eq.) and Et₃N (0.1 eq.), then the mixture may be stirredat 25° C. for 16 h under N₂ atmosphere. The mixture may be added NaBH₄(1.5 eq.) at 0° C., and stirred at 25° C. for 2 h. The reaction mixturemay be quenched with H₂O at 25° C. and concentrated under reducedpressure. The residue may be purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=0:1) to yield the reductive amination product.

A mixture of SEM protected conjugated imidazole (1 eq.) in TFA and DCMmay be stirred at 20° C. for 1 h. The reaction mixture may beconcentrated under reduced pressure to remove DCM at 25° C. The residuemay be diluted with EtOH and stirred at 60° C. for 3 h. The mixture maybe concentrated under reduced pressure. The residue may be purified byprep-HPLC (TFA condition). (column: Welch Ultimate AQ-C18 150*30 mm*5um; mobile phase: [water(0.1% TFA)-ACN]; B %: 18%-48%, 12 min) to yieldthe deprotection of SEM group product.

To a solution of ester (1 eq.) in 2:1 MeOH:H₂O, may be added LiOH (3eq.). The mixture may be stirred at 50° C. for 2 h. The mixture may beconcentrated under reduced pressure. The residue may be adjusted pH=2with HCl (6M) and extracted with EtOAc (2×). The combined organic layersmay be dried over Na₂SO₄, filtered and concentrated under reducedpressure to yield the hydrolysis reaction product.

To a solution of amine (1 eq.) in n-BuOH may be added TsOH (3 eq.) and2-bromo-1H-imidazole (5 eq.). The mixture may be stirred at 140° C. for12 h. The reaction mixture may be concentrated under reduced pressureand purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10um; mobile phase: [water(0.1% TFA)-ACN]; B %: 30%-90%, 10 min) to yieldthe substitution reaction product.

To a solution of amine (1 eq.) in MeCN may be added CuBr₂ (0.4 eq.) andtert-butyl nitrite (1.5 eq.). The mixture may be stirred at 60° C. for 1h and concentrated. The residue may be diluted with H₂O and extractedwith EtOAc (3×). The combined organic layers may be dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue may be purified by prep-TLC (SiO₂, petroleum ether:ethylacetate=1:2) to yield the Sandmeyer reaction product.

Definitions

The articles “a” and “an” are used in this application to refer to oneor more than one (i.e., at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this application to mean either “and” or“or” unless indicated otherwise.

The term “halo” or “halogen” as used herein includes fluoro, chloro,bromo, and iodo.

The term “alkyl,” as used herein, refers to saturated, straight orbranched-chain hydrocarbon radicals containing, In some embodiments,between one and six carbon atoms. Examples of C₁-C₈ alkyl radicalsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, andn-hexyl radicals.

The term “alkoxy” means an alkyl radical attached through an oxygenlinking atom, represented by —O-alkyl. For example, “(C₁-C₄) alkoxy”includes methoxy, ethoxy, propoxy, and butoxy.

The terms “haloalkyl” and “haloalkoxy” means alkyl or alkoxy, as thecase may be, substituted with one or more halogen atoms.

An “alkylene group” is a saturated aliphatic branched or straight-chaindivalent hydrocarbon radical. Unless otherwise specified, an alkylenegroup typically has 1-6 carbon atoms, e.g., (C₁-C₆) alkylene.

The term “cycloalkyl” means a monocyclic saturated hydrocarbon ringsystem. For example, C₃-C₇ cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl, cycloheptyl.

A bridged cycloalkyl means a bicyclic hydrocarbon ring system in whichthe two rings share at least three adjacent ring carbon atoms. Forexample, a bridged cycloalkyl has 6-12 ring carbon atoms. Examplesinclude, but are not limited to, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bomenyl, norbomyl,norbomenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, and adamantyl.

The terms “heterocyclyl”, “heterocyclic ring”, and “heterocyclic group”,are used interchangeably herein, and means saturated or unsaturatednon-aromatic 4-10 membered ring radical containing from 1 to 4 ringheteroatoms, which may be the same or different, selected from N, O, orS. It can be monocyclic, bicyclic or tricyclic (e.g., a fused or bridgedbicyclic or tricyclic ring). Examples of include, but are not limitedto, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl,pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl,dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl,dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.A heterocyclic ring optionally contains one or more double bonds and/oris optionally fused with one or more aromatic rings (for example,tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole,imidazopyrimidine, quinolinone, dioxaspirodecane). Examples of 3-7membered monocyclic heterocyclic ring include, but are not limited to,azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl,piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl,oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl,dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl,dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl,tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.

A bridged heterocyclyl means a bicyclic ring system containing from 1 to4 ring heteroatoms in which the two rings share at least three adjacentring atoms. For example, a bridged heterocyclyl has 6-12 ring atoms.Examples include, but are not limited to, azanorbornyl, quinuclidinyl,isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl,azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.1]octanyl,azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl,azabicyclo[3.3.0]nonanyl, and azabicyclo [3.3.1]nonanyl.

The terms “heteroaryl”, “heteroaromatic”, “heteroaryl ring”, “heteroarylgroup”, “heteroaromatic ring”, and “heteroaromatic group”, are usedinterchangeably herein. “Heteroaryl”, when used alone or as part of alarger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers toaromatic ring groups having five to ten ring atoms selected from carbonand at least one (typically 1 to 4, more typically 1 or 2) heteroatoms(e.g., oxygen, nitrogen, or sulfur). “Heteroaryl” includes monocyclicrings and polycyclic rings in which a monocyclic heteroaromatic ring isfused to one or more other aromatic or heteroaromatic rings.“Heteroaryl” includes monocyclic and bicyclic ring systems.

“Monocyclic 5-6 membered heteroaromatic ring (or heteroaryl)” means amonocyclic heteroaromatic ring having five or six ring atoms selectedfrom carbon and at least one (typically 1 to 3, more typically 1 or 2)heteroatoms (e.g., oxygen, nitrogen, or sulfur). Examples of monocyclic5-6 membered heteroaromatic ring groups include furanyl (e.g.,2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl,5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl),pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), thiazolyl (e.g.,2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, triazolyl (e.g.,2-triazolyl, 5-triazolyl), tetrazolyl (e.g., tetrazolyl), and thienyl(e.g., 2-thienyl, 3-thienyl).

If a group is described as being “substituted,” a non-hydrogensubstituent replaces a hydrogen atom on a carbon or nitrogen. Thus, forexample, a substituted alkyl is an alkyl wherein at least onenon-hydrogen substituent is in the place of a hydrogen atom on the alkylsubstituent. To illustrate, monofluoroalkyl is alkyl substituted with afluoro substituent, and difluoroalkyl is alkyl substituted with twofluoro substituents. It should be recognized that if there is more thanone substitution on a substituent, each non-hydrogen substituent can beidentical or different (unless otherwise stated). As used herein, manymoieties (e.g., alkyl, cycloalkyl, or a heterocyclic ring) are referredto as being either “substituted” or “optionally substituted”. It will beappreciated that the phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.” When amoiety is modified by one of these terms, unless otherwise noted, itdenotes that any portion of the moiety that is known to one skilled inthe art as being available for substitution can be substituted, whichincludes one or more substituents. If more than one substituent ispresent, then each substituent is independently selected. Such means forsubstitution are well-known in the art and/or taught by the instantapplication. The optional substituents can be any substituents that aresuitable to attach to the moiety. A person of ordinary skill in the artwill recognize that the compounds and definitions provided do notinclude impermissible substituent patterns (e.g., methyl substitutedwith 5 different groups, and the like). Such impermissible substitutionpatterns are clearly recognized by a person of ordinary skill in theart. When a group is described as being optionally substituted by “oneor more” substituents, it denotes that the group is optionallysubstituted by one, two, three, four, five or six substituents. In someembodiments, a group is optionally substituted by 1-3 substituents. Insome embodiments, a group is optionally substituted by 1-2 substituents.In some embodiments, a group is optionally substituted by onesubstituent.

Suitable substituents are those which do not have a significant adverseeffect on the ability of the compound to inhibit RAD51. Where suitablesubstituents are not specifically enumerated, exemplary substituentsinclude, but are not limited to, halo, CN, alkyl, alkoxy, halomethyl,halomethoxy, (C₁-C₅)alkyl, halo(C₁-C₅)alkyl, (C₁-C₅)alkoxy, NO₂,OR^(c′), NR^(a′)R^(b′), S(O)_(i)R^(a′), NR^(a)S(O)_(i)R^(b′),S(O)_(i)NR^(a′)R^(b′), C(═O)OR^(a′), OC(═O)OR^(a′), C(═S)OR^(a′),O(C═S)R^(a′), C(═O)NR^(a′)R^(b′), NR^(a′)C(═O)R^(b′),C(═S)NR^(a′)R^(b′), NR^(a′)C(═S)R^(b′), NR^(a′)(C═O)OR^(b′),O(C═O)NR^(a′)R^(b′), NR^(a′)(C═S)OR^(b′), O(C═S)NR^(a′)R^(b′),NR^(a′)(C═O)NR^(a′)R^(b′), NR^(a′)(C═S)NR^(a′)R^(b′), C(═S)R^(a′),C(═O)R^(a′), (C₃-C₆) cycloalkyl, monocyclic heteroaryl, and phenyl,wherein the (C₃-C₆) cycloalkyl, monocyclic heteroaryl, and phenylsubstituents are optionally and independently substituted, for example,with CH₃, halomethyl, halo, methoxy, or halomethoxy. Each R^(a′) andeach R^(b′) are independently H or (C₁-C₆) alkyl, wherein the (C₁-C₆)alkyl group represented by R^(a′) or R^(b′) is optionally substituted,for example, with hydroxyl or (C₁-C₃) alkoxy; R^(c′) is H, halo(C₁-C₆)alkyl, or (C₁-C₆) alkyl, wherein the (C₁-C₆) alkyl group represented byR^(c) is optionally substituted, for example with hydroxyl or (C₁-C₃)alkoxy; and i is 0, 1, or 2. ═O is also a suitable substituent foralkyl, cycloalkyl, and a heterocyclic ring.

Suitable substituents may also include: —F, —Cl, —Br, —I, —OH, protectedhydroxy, —NO₂, —CN, —NH₂, protected amino, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkenyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkenyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl,—O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₁₂-alkenyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl,—C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂, —CONH—C₁-C₁₂-alkyl,—CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,—OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkenyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkenyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, NHC(O)NH-heterocycloalkyl, —NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NHheterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkenyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkenyl,C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NHheterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkenyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkenyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkenyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” or “therapeutically effective amount” when used inconnection with a compound or pharmaceutical composition is an amounteffective for treating or preventing a disease in a subject as describedherein.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The compounds of the present application, or a pharmaceuticallyacceptable salt or solvate thereof, can also be used to prevent adisease, condition or disorder. As used herein, “preventing” or“prevent” describes reducing or eliminating the onset of the symptoms orcomplications of the disease, condition or disorder.

The term “disorder” is used in this application to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

As used herein, the term diseases or disorders in which RAD51 plays arole means any disease or other deleterious condition in which RAD51 isknown to play a role. Accordingly, another embodiment of the presentapplication relates to treating or lessening the severity of one or morediseases in which RAD51 is known to play a role.

Pharmaceutical Compositions

The compounds disclosed therein are RAD51 inhibitors. The pharmaceuticalcomposition of the present application comprises one or more RAD51inhibitors, or a pharmaceutically acceptable salt or solvate thereof,and a pharmaceutically acceptable carrier or diluent.

A “pharmaceutical composition” is a formulation containing the compoundof the present application in a form suitable for administration to asubject. In some embodiments, the pharmaceutical composition is in bulkor in unit dosage form. The unit dosage form is any of a variety offorms, including, for example, a capsule, an IV bag, a tablet, a singlepump on an aerosol inhaler or a vial. The quantity of active ingredient(e.g., a formulation of the disclosed compound or a pharmaceuticallyacceptable salt or solvate thereof) in a unit dose of composition is aneffective amount and is varied according to the particular treatmentinvolved. One skilled in the art will appreciate that it is sometimesnecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration. A variety of routes are contemplated, including oral,pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous,intramuscular, intraperitoneal, inhalational, buccal, sublingual,intrapleural, intrathecal, intranasal, and the like. Dosage forms forthe topical or transdermal administration of a compound of thisapplication include powders, sprays, ointments, pastes, creams, lotions,gels, solutions, patches and inhalants. In some embodiments, the activecompound is mixed under sterile conditions with a pharmaceuticallyacceptable carrier, and with any preservatives, buffers or propellantsthat are required.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, carriers, and/or dosage forms whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessivetoxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable carrier” and “pharmaceutically acceptablediluent” refer to a substance that aids the formulation and/oradministration of an active agent to and/or absorption by a subject andcan be included in the compositions of the present application withoutcausing a significant adverse toxicological effect on the subject.Non-limiting examples of pharmaceutically acceptable carriers and/ordiluents include water, NaCl, normal saline solutions, lactatedRinger's, normal sucrose, normal glucose, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions(such as Ringer's solution), alcohols, oils, gelatins, carbohydratessuch as lactose, amylose or starch, fatty acid esters,hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.Such preparations can be sterilized and, if desired, mixed withauxiliary agents such as lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure, buffers,coloring, and/or aromatic substances and the like that do notdeleteriously react with or interfere with the activity of the compoundsprovided herein. One of ordinary skill in the art will recognize thatother pharmaceutical excipients are suitable for use with disclosedcompounds.

The term “carrier”, as used in this application, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The pharmaceutical compositions of the present teachings optionallyinclude one or more pharmaceutically acceptable carriers and/or diluentstherefor, such as lactose, starch, cellulose and dextrose. Otherexcipients, such as flavoring agents; sweeteners; and preservatives,such as methyl, ethyl, propyl and butyl parabens, can also be included.More complete listings of suitable excipients can be found in theHandbook of Pharmaceutical Excipients (5^(th) Ed., Pharmaceutical Press(2005)). A person skilled in the art would know how to prepareformulations suitable for various types of administration routes.Conventional procedures and ingredients for the selection andpreparation of suitable formulations are described, for example, inRemington's Pharmaceutical Sciences (2003-20^(th) edition) and in TheUnited States Pharmacopeia: The National Formulary (USP 24 NF19)published in 1999. The carriers, diluents and/or excipients are“acceptable” in the sense of being compatible with the other ingredientsof the pharmaceutical composition and not deleterious to the recipientthereof.

Pharmaceutical compositions of the application are formulated to becompatible with its intended route of administration. Examples of routesof administration include parenteral, e.g., intravenous, intradermal,subcutaneous, oral (e.g., inhalation), transdermal (topical), andtransmucosal administration. Solutions or suspensions used forparenteral, intradermal, or subcutaneous application can include thefollowing components: a sterile diluent such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates, and agents for theadjustment of tonicity such as sodium chloride or dextrose. The pH canbe adjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

A compound or pharmaceutical composition of the application can beadministered to a subject in many of the well-known methods currentlyused for chemotherapeutic treatment. For example, for treatment ofcancers, a compound of the application may be injected directly intotumors, injected into the blood stream or body cavities or taken orallyor applied through the skin with patches. The dose chosen should besufficient to constitute effective treatment but not as high as to causeunacceptable side effects. The state of the disease condition (e.g.,cancer, precancer, and the like) and the health of the patient shouldpreferably be closely monitored during and for a reasonable period aftertreatment.

The term “therapeutically effective amount”, as used herein, refers toan amount of a pharmaceutical agent to treat, ameliorate, or prevent anidentified disease or condition, or to exhibit a detectable therapeuticor inhibitory effect. The effect can be detected by any assay methodknown in the art. The precise effective amount for a subject will dependupon the subject's body weight, size, and health; the nature and extentof the condition; and the therapeutic or combination of therapeuticsselected for administration. Therapeutically effective amounts for agiven situation can be determined by routine experimentation that iswithin the skill and judgment of the clinician.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays, e.g., of neoplastic cells, orin animal models, usually rats, mice, rabbits, dogs, or pigs. The animalmodel may also be used to determine the appropriate concentration rangeand route of administration. Such information can then be used todetermine useful doses and routes for administration in humans.Therapeutic/prophylactic efficacy and toxicity may be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., ED₅₀ (the dose therapeutically effective in 50% of thepopulation) and LD₅₀ (the dose lethal to 50% of the population). Thedose ratio between toxic and therapeutic effects is the therapeuticindex, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceuticalcompositions that exhibit large therapeutic indices are preferred. Thedosage may vary within this range depending upon the dosage formemployed, sensitivity of the patient, and the route of administration.

Dosage and administration are adjusted to provide sufficient levels ofthe active agent(s) or to maintain the desired effect. Factors which maybe taken into account include the severity of the disease state, generalhealth of the subject, age, weight, and gender of the subject, diet,time and frequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

The pharmaceutical compositions containing active compound (i.e., acompound of Formula (I)) of the present application may be manufacturedin a manner that is generally known, e.g., by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, or lyophilizing processes. Pharmaceuticalcompositions may be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers comprising excipients and/orauxiliaries that facilitate processing of the active compound intopreparations that can be used pharmaceutically. Of course, theappropriate formulation is dependent upon the route of administrationchosen.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringeability exists. It must be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in an appropriate solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, methods of preparation are vacuum dryingand freeze-drying that yields a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral compositions generally include an inert diluent or an ediblepharmaceutically acceptable carrier. They can be enclosed in gelatincapsules or compressed into tablets. For the purpose of oral therapeuticadministration, the active compound can be incorporated with excipientsand used in the form of tablets, troches, or capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash,wherein the compound in the fluid carrier is applied orally and swishedand expectorated or swallowed. Pharmaceutically compatible bindingagents, and/or adjuvant materials can be included as part of thecomposition. The tablets, pills, capsules, troches and the like cancontain any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate or Sterotes; a glidant such as colloidal silicondioxide; a sweetening agent such as sucrose or saccharin; or a flavoringagent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compound is delivered in the formof an aerosol spray from pressured container or dispenser, whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compound is formulated intoointments, salves, gels, or creams as generally known in the art.

The active compound can be prepared with pharmaceutically acceptablecarriers that will protect the compound against rapid elimination fromthe body, such as a controlled release formulation, including implantsand microencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid.Methods for preparation of such formulations will be apparent to thoseskilled in the art. The materials can also be obtained commercially fromAlza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions(including liposomes targeted to infected cells with monoclonalantibodies to viral antigens) can also be used as pharmaceuticallyacceptable carriers. These can be prepared according to methods known tothose skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

It is especially advantageous to formulate oral or parenteralcompositions in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the subject tobe treated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the application are dictated by anddirectly dependent on the unique characteristics of the active compoundand the particular therapeutic effect to be achieved.

In therapeutic applications, the dosages of the pharmaceuticalcompositions used in accordance with the application vary depending onthe agent, the age, weight, and clinical condition of the recipientpatient, and the experience and judgment of the clinician orpractitioner administering the therapy, among other factors affectingthe selected dosage. Generally, the dose should be sufficient to resultin slowing, and preferably regressing, the growth of the tumors and alsopreferably causing complete regression of the cancer. Dosages can rangefrom about 0.01 mg/kg per day to about 5000 mg/kg per day. An effectiveamount of a pharmaceutical agent is that which provides an objectivelyidentifiable improvement as noted by the clinician or other qualifiedobserver. For example, regression of a tumor in a subject may bemeasured with reference to the diameter of a tumor. Decrease in thediameter of a tumor indicates regression. Regression is also indicatedby failure of tumors to reoccur after treatment has stopped. As usedherein, the term “dosage effective manner” refers to amount of an activecompound to produce the desired biological effect in a subject or cell.

The pharmaceutical compositions can be included in a container, pack, ordispenser together with instructions for administration.

The dosage regimen utilizing the compound is selected in accordance witha variety of factors including type, species, age, weight, sex andmedical condition of the patient; the severity of the condition to betreated; the route of administration; the renal and hepatic function ofthe patient; and the particular compound or pharmaceutically acceptablesalt or solvate thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Techniques for formulation and administration of the disclosed compoundof the application can be found in Remington: the Science and Practiceof Pharmacy, 19^(th) edition, Mack Publishing Co., Easton, Pa. (1995).In an embodiment, the compound described herein, and thepharmaceutically acceptable salts or solvates thereof, are used inpharmaceutical preparations in combination with a pharmaceuticallyacceptable carrier or diluent. Suitable pharmaceutically acceptablecarriers include inert solid fillers or diluents and sterile aqueous ororganic solutions. The compound or pharmaceutically acceptable salts orsolvates thereof will be present in such pharmaceutical compositions inamounts sufficient to provide the desired dosage amount in the rangedescribed herein.

All percentages and ratios used herein, unless otherwise indicated, areby weight. Other features and advantages of the present application areapparent from the different examples. The provided examples illustratedifferent components and methodology useful in practicing the presentapplication. The examples do not limit the claimed application. Based onthe present application the skilled artisan can identify and employother components and methodology useful for practicing the presentapplication.

Methods of Using the Compounds

The present application provides a method of treating a subject with adisease or disorder which can be ameliorated by inhibition of RAD51, byadministering to the subject an effective amount of one or moredisclosed compounds, or a pharmaceutically acceptable salt or solvatethereof, or the corresponding pharmaceutical composition. Diseases whichcan be ameliorated by inhibition of RAD51 include treating cancer,autoimmune disease, immune deficiency, or neurodegenerative disease.

The present application further relates to a method of treating adisease or disorder in which RAD51 plays a role, for example, cancer, anautoimmune disease, an immune deficiency, or a neurodegenerativedisease. The method comprises administering to a subject in need thereofan effective amount of a compound disclosed herein or a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutical compositiondisclosed herein.

In one aspect, described herein is a method of treating cancer,autoimmune disease, immune deficiency, or neurodegenerative disease, themethod comprising administering a therapeutically effective dose of acomposition as described herein, e.g., a composition comprising acompound of the present application, to a subject in need of treatmentfor cancer, autoimmune disease, immune deficiency, or neurodegenerativedisease.

In some embodiments, described herein is a method of treating cancercomprising administering a therapeutically effective dose of acomposition as described herein, e.g., a composition comprising acompound of the present application, to a subject in need of treatmentfor cancer.

In some embodiments, described herein is a method of treating autoimmunedisease comprising administering a therapeutically effective dose of acomposition as described herein, e.g., a composition comprising acompound of the present application, to a subject in need of treatmentfor autoimmune disease.

In some embodiments, described herein is a method of treating immunedeficiency comprising administering a therapeutically effective dose ofa composition as described herein, e.g., a composition comprising acompound of the present application, to a subject in need of treatmentfor immune deficiency.

In some embodiments, described herein is a method of treatingneurodegenerative disease comprising administering a therapeuticallyeffective dose of a composition as described herein, e.g., a compositioncomprising a compound of the present application, to a subject in needof treatment for neurodegenerative disease.

The present application further relates to use of a compound disclosedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of a disease or disorder in which RAD51plays a role, for example, a cancer, an autoimmune disease, an immunedeficiency, or a neurodegenerative disease.

The present application provides use of a compound disclosed herein, ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of a disease or disorder which can beameliorated by inhibition of RAD51.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of a cancer, autoimmune disease, immunedeficiency, or neurodegenerative disease.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of a cancer.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of an autoimmune disease.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of an immune deficiency.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in the manufacture of amedicament for the treatment of a neurodegenerative disease.

The present application further relates to a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, for use in treating adisease or disorder in which RAD51 plays a role, for example, a cancer,an autoimmune disease, an immune deficiency, or a neurodegenerativedisease.

The present application provides a compound disclosed herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition disclosed herein, for use in treating a disease or disorderwhich can be ameliorated by inhibition of RAD51.

In one aspect, described herein is a compound disclosed herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition disclosed herein, for use in treating a cancer, autoimmunedisease, immune deficiency, or neurodegenerative disease.

In one aspect, described herein is a compound disclosed herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition disclosed herein, for use in treating a cancer.

In one aspect, described herein is a compound disclosed herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition disclosed herein, for use in treating an autoimmune disease.

In one aspect, described herein is a compound disclosed herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition disclosed herein, for use in treating an immune deficiency.

In one aspect, described herein is a compound disclosed herein, or apharmaceutically acceptable salt or solvate thereof, or a pharmaceuticalcomposition disclosed herein, for use in treating a neurodegenerativedisease.

The present application further relates to use of a compound disclosedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating a disease ordisorder in which RAD51 plays a role, for example, a cancer, anautoimmune disease, an immune deficiency, or a neurodegenerativedisease.

The present application provides use of a compound disclosed herein, ora pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating a disease ordisorder which can be ameliorated by inhibition of RAD51.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating a cancer,autoimmune disease, immune deficiency, or neurodegenerative disease.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating a cancer.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating an autoimmunedisease.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating an immunedeficiency.

In one aspect, described herein is use of a compound disclosed herein,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition disclosed herein, in treating aneurodegenerative disease.

In some embodiments, the subject can be a subject determined to have anincreased level of DNA damage occurring in one or more cell typesrelative to a reference level. As used herein, “DNA damage” refers tobreaks, nicks, and mutations of the DNA present in a cell. In someembodiments, the DNA damage can comprise one or more of single-strandbreaks (e.g., “nicks”), double strand breaks (DSBs), and mutations. Insome embodiments, the DNA damage can be one or more DSBs. As usedherein, “mutation” refers to a change or difference in the geneticmaterial of a cell as compared to a reference wildtype cell, e.g., adeletion, an insertion, a SNP, a gene rearrangement, and/or theintroduction of an exogenous gene or sequence.

In some embodiments, the subject can be determined to have an increasedlevel of DNA damage if the subject is determined to have an increasedlevel and/or activity of a DNA damage process or DNA editing enzyme. Asused herein, “DNA damage process” refers to any activity or process in acell which causes one or more types of DNA damage to occur.

In some embodiments, an increased level of DNA damage can be anincreased level of mutations, e.g., by determining the overall mutationstatus in all or a portion of the genome of a cell. An overall mutationstatus at least 2% greater, e.g., 2% greater or more, 3% greater ormore, 5% greater or more, 10% greater or more, or 20% greater or morethan the overall mutation status in a reference cell can be indicativeof an increased, elevated, and/or significant level of a DNA editingenzyme activity. In some embodiments, the level of hyper mutations canbe determined. In some embodiments, the overall mutation status in thewhole genome or a portion thereof can be determined using FISH, wholegenome sequencing, high throughput sequencing, exome sequencing,hybridization, and/or PCR. In some embodiments the activity of a DNAediting enzyme can be measured by determining the level ofhypermutations in the specific target genes including, but not limitedto IGH, BCL6, MYC, BCLl 1A, CD93, PIMl and/or PAX5. In some embodimentsthe DNA editing enzyme is AID. In some embodiments, a level of mutationin specific target genes including IGH, BCL6, MYC, BCLl 1A, CD93, PIMland/or PAX5 which is at least 2% greater, e.g., 2% greater or more, 3%greater or more, 5% greater or more, 10% greater or more, or 20% greateror more than the level of mutation in IGH, BCL6, MYC, BCLl 1A, CD93,PIMl and/or PAX5 in a reference cell can be indicative of an increased,elevated, and/or significant level of AID activity.

In some embodiments, an increased level of DNA damage can be anincreased level of double strand breaks (DSBs). The level of DSBs can bedetermined, by way of non-limiting example, by karyotyping, by γ-H2AXfoci formation, and/or by using FISH analysis to detect DNA doublestrand breaks, e.g., DNA breakage detection fish (DBD-FISH) (Volpi andBridger, BioTechniques, Vol. 45, No. 4, October 2008, pp. 385-409).

In some embodiments, an increased level of DNA damage can be anincreased level of single strand breaks. The level of single-strandbreaks in DNA can be determined, by way of non-limiting example, byCOMET assays, FISH, or the use of single-strand break-specific probes.Detection of DNA breaks, both single and double-stranded is known in theart and described further, at, e.g., Kumari et al., EXCLI Journal 20097:44-62 and Motalleb et al., Research Journal of Applied Sciences,Engineering and Technology 2012 4: 1888-1894; each of which isincorporated by reference herein in its entirety.

In some embodiments, an increased level of activity of a DNA damageprocess can comprise an increased level and/or activity of a DNA editingenzyme. In some embodiments, the technology described herein is directedto treating cells having an active DNA editing enzyme with a compound ofthe present application. In some embodiments, the technology describedherein is directed to treating cells having an increased level and/oractivity of a DNA editing enzyme with a compound of the presentapplication. As used herein, “DNA editing enzyme” refers to an enzymewhich normally catalyzes the mutation, exchange or excision of DNAsegments, particularly enzymes which can generate or promote thegeneration of point mutations, DNA single strand breaks, DNAdouble-strand breaks or protein-DNA adducts. A DNA editing enzyme, asreferred to herein, is not necessarily site-specific in its action.Similarly, it is not necessarily cell specific. In some embodiments, thecell is a B cell expressing a detectable amount of such an enzyme.

Non-limiting examples of DNA editing enzymes include, but are notlimited to Recombination Activating Gene 1 (RAG1; NCBI Gene ID: 5896),Recombination Activating Gene 1 (RAG2; NCBI Gene ID: 5897),Sporulation-specific protein 11 (SPO1 1; NCBI Gene ID: 23626), APOBECfamily members a Type 1 Topoisomerase; a Type 2 Topoisomerase; and/orAID. In some embodiments, the DNA editing enzyme can be AID.

In some embodiments, the DNA editing enzyme can be a member of theAPOBEC (apolipoprotein B mRNA editing enzyme, catalyticpolypeptide-like) family. As used herein “APOBEC family” refers to afamily of cytidine deaminase enzymes having an N-terminal zinc-dependentcytidine deaminase catalytic domain comprising and a C-terminalpseudocatalytic domain. Non-limiting examples of APOBEC family membersinclude AID, APOBEC 1 (e.g., NCBI Gene ID: 339), APOBEC2 (e.g., NCBIGene ID: 10930), APOBEC3A (e.g., NCBI Gene ID: 200315), APOBEC3B (e.g.,NCBI Gene ID: 9582), APOBEC3C (e.g., NCBI Gene ID: 27350), APOBEC3E(e.g., NCBI Gene ID: 140564), APOBEC3F (e.g., NCBI Gene ID:200316),APOBEC3G (e.g., NCBI Gene ID: 60489), APOBEC3H (e.g., NCBI Gene ID:164668), and APOBEC4 (e.g., NCBI Gene ID: 403314).

In some embodiments, the DNA editing enzyme can be a Type 1topoisomerase. In some embodiments, the DNA editing enzyme can be a Type2 topoisomerase. Topoisomerases generate breaks in DNA to help uncoil orrelax the strand. Type II topoisomerases hydrolyze ATP to generate DSBcuts, while Type I topoisomerases generate single-stranded breaks.Non-limiting examples of Type II topoisomerases can includetopoisomerase II (e.g., NCBI Gene ID: 7153 and 7155). Non-limitingexamples of Type I topoisomerases can include topoisomerase I (e.g.,NCBI Gene ID: 7150).

Embodiments of the technology described herein are based on thediscovery that the compounds described herein can inhibit DNA repairmechanisms, e.g., homologous recombination repair. Activation-inducedcytidine deaminase (AID, or AICDA, also known as ARP2, CDA2 or HIGM2), aDNA-editing enzyme that is a member of the apolipoprotein B mRNA editingenzymes, catalytic polypeptide-like (APOBEC), will cause widespreadgenomic breaks and cell death in cells with diminished homologousrecombination ability (e.g., cells with diminished DNA double strandbreak repair abilities). Accordingly, provided herein is a method ofcausing cell death comprising detecting increased expression of aDNA-editing enzyme (e.g., AID) in a cell and thereafter contacting thecell with a compound of the present application; thereby resulting incell death. Accordingly, provided herein is a method of causing celldeath comprising increasing expression of a DNA-editing enzyme (e.g.,AID) in a cell and thereafter contacting the cell with a compound of thepresent application; thereby resulting in cell death. Accordingly,provided herein is a method of causing cell death comprisingadministering to a cell a therapeutically effective amount of a DNAediting enzyme (e.g., AID) and thereafter contacting the cell with acompound of the present application; thereby resulting in cell death.

AID, encoded by the AICDA gene (NCBI Gene ID: 57379), is required forproper B-cell function and is most prominently expressed in centroblastB-cells. The protein is involved in somatic hypermutation, geneconversion, and class-switch recombination of immunoglobulin genes. AIDis normally expressed almost exclusively in antigen-activated germinalcenter B-cells, where it initiates immunoglobulin isotype classswitching (Manis et al., 2002, Trends Immunol, 23, 31-39; Chaudhuri andAlt, Nat Rev Immunol, 2004, 4, 541-552; Longerich et al., Curr OpinImmunol, 2006, 18, 164-174; Chaudhuri et al., Adv Immunol 2007, 94,157-214). AID is required for somatic hypermutation and immunoglobulinclass switching in activated B cells. AID expression is regulated byCD40 ligand, B-cell receptor, IL4R, or Toll-like receptor stimulation(Crouch et al., J Exp Med 2007 204: 1145-1156; Muramatsu et al., J BiolChem 1999 274: 18470-6). After activation, AID is transientlyupregulated, induces point mutations or DNA double strand breaks in asequence nonspecific manner within immunoglobulin genes, and is thendownregulated (Longerich et al., Curr Opin Immunol, 2006, 18, 164-176;Chaudhuri et al., Adv Immunol 2007, 94, 157-214). Overall, AID is activein only a tiny population of normal cells (antigen-activated B-cells) atany given time. The genomic rearrangements and mutations controlled byAID lead to the development of antigen-recognition diversity, receptorediting and lymphoid effector function required for functional adaptiveimmunity (Mills, et al., Immunol Rev 2003 194:77-95). It has beenreported that AID has off-target point mutation activities (Liu, M. etal., Nature 2008, 451, 841-845; Liu and Schatz, Trends Immunol. 2009,30, 173-181; Perez-Duran et al., Carcinogenesis. 2007, 28(12):2427-33).Robbiani et al. has reported off-target activities of AID in B-cells,especially c-myc/IgH translocations (Robbiani et al., Mol Cell 2009,36(4):631-41). AID expression accelerates the rate of tumor developmentin Bcl6 transgenic mice (Pasqualucci et al., 2008, Nat. Genet. 40,108-112). However, deregulated AID does not necessarily cause malignancyor translocation-associated cancer on its own in B cells (Muto et al.,2006, Proc. Natl. Acad. Sci. USA 103, 2752-2757; Okazaki et al., 2003,J. Exp. Med. 197, 1173-1181; Shen et al., 2008, Mol. Immunol. 45,1883-1892). In addition, despite its role in promoting c-myc/IgHtranslocation, AID is not required for the development of plasmacytosisor plasmacytoma in IL-6 transgenic or pristane-treated mice,respectively (Kovalchuk et al., 2007, J. Exp. Med. 204, 2989-3001;Ramiro et al., 2004, J. Exp. Med. 200, 1103-1110). However, most human Bcell lymphoma-associated translocations do not involve c-myc, and manydo not involve Ig genes (Kuppers, 2005, Oncogene 20, 5580-5594).

Overexpression of AID has been reported in chronic lymphocytic leukemia(CLL) (Hancer et al., Leuk Lymphoma. 2011 January; 52(1):79-84; Heintelet al., Leukemia. 2004 April; 18(4):756-62). Further, AID expression hasbeen shown to be correlated with blast crisis B lineage leukemia andtherapy resistance in myeloid leukemia and to be associated withgenerally poor prognosis in chronic B lymphocytic leukemia (Mao et al.,Br J Dermatol 2001, 145: 117-122; Chaudhuri et al., Nature 2004,430:992-8). Further expression of AID in tumor cells from a variety ofcancers has been reported including but not limited to lung, breast,gastric, colon, intestinal, liver cancer and choriangiocarcinoma (Greeveet al., Blood 2003, 1010, 3574-3580; Feldhahn et al., J Exp Med 2007,204, 1157-1166; Kotani et al., PNAS USA 2007, 104, 1616-1620; Engels etal., 2008, Appl Immunohistochem Mol Morphol 16, 521-529; Klemm et al.,2009, Cancer Cell 6, 232-245; Palacios et al., 2010, Blood 115(22),4488-4496; Leuenberger et al., 2009, Mod Pathol 32, 177-186; Gruber etal., 2010, Cancer Res 70, 7411-7420; inflammatory cancer (Marusawa 2008,Int J Biochem Cell Biol.40, 399-402); follicular lymphoma (Hardianti etal., 2004, Leukemia 18, 826-831; Shikata et al., 2012, Cancer Sci.103(3):415-21); thyroid cancer (Qiu et al., 2012, Mod Pathol 25(1),36-45); breast cancer (Borchert et al., 2011, BMC Cancer 11:347);Marusawa, et al., 2011, Adv Immunol 111: 109-41; Zhang et al., 2012, HumPathol 43(3):423-34; Komori et al., 2008, Hepatology 47(3):888-896;Hockley 2010, Leukemia 24(5): 1084-6; adult T-cell leukemia (Nakamura etal., 2011, Br J Dermatol. 165(2):437-9). All of the references in theforegoing paragraph are incorporated by reference herein in theirentireties.

Elevated levels of AID have been reported in arthritis (Xu et al.,Scand. J. Immunol. 2009, 296, 2033-6) and in the MRL/Fas(lpr/lpr) mouselupus model (White et al., 2011, Autoimmunity 44(8), 585-98). All of thereferences in the foregoing paragraph are incorporated by referenceherein in their entireties.

When DSB repair is inhibited, the extent of the DSBs generated by AID ismuch higher than previously suspected and the extent of genomic damageis so severe as to result in cell death. Accordingly, In someembodiments of the technology described herein, there is provided amethod of treatment comprising; (a) selecting a subject having cellsthat express elevated levels of activation-induced cytidine deaminase(AID); and (b) administering a therapeutically effective amount of aninhibitor of double strand break repair (e.g., a compound of the presentapplication) to the subject; wherein an elevated level of AID is a levelof AID that is higher than the level of AID in cells of the same typefrom a healthy individual. In some embodiments, the cells expressingelevated levels of AID are B cells. In some embodiments, the B cellexpressing elevated levels of AID is a cancerous B cells or a B cellassociated with autoimmune disease. In some embodiments, the subject canbe a human subject.

Methods provided herein treat cancers, autoimmune disorders, immunedeficiencies, or neurodegenerative disorders by inhibiting DNA doublestrand break repair. This inhibition proves lethal to cells expressingAID, as AID generates widespread genomic breaks, and the treatment witha double strand break repair inhibitor prevents the repair of theselesions which are being generated by the cell itself. This results incell death in the subject which is specific to the cells expressing AID,e.g., cancerous B cells and/or autoimmune cells. Accordingly, asdescribed herein, In some embodiments there is a provided a treatmentparadigm that selectively induces self-destruction of certain diseasedcells, while reducing the unintended side effects in healthy tissues.

In some embodiments, an increased level and/or activity of a DNA editingenzyme can be an increased level of DNA editing enzyme mRNA. mRNA levelscan be assessed using, e.g., biochemical and molecular biologytechniques such as Northern blotting or other hybridization assays,nuclease protection assay, reverse transcription (quantitative RT-PCR)techniques, RNA-Seq, high throughput sequencing and the like. Suchassays are well known to those in the art. In some embodiments, nuclear“run-on” (or “run-off) transcription assays are used (see e.g., Methodsin Molecular Biology, Volume: 49, Sep. 27, 1995, Page Range: 229-238).Arrays can also be used; arrays, and methods of analyzing mRNA usingsuch arrays have been described previously, e.g., in EP0834575,EP0834576, W096/31622, U.S. Pat. No. 5,837,832 or WO98/30883. WO97/10365provides methods for monitoring of expression levels of a multiplicityof genes using high density oligonucleotide arrays.

In some embodiments, a subject can be determined to have an increasedlevel of DNA damage occurring in one or more cell types relative to areference level if the subject has been exposed to an agent that isknown to cause such DNA damage. Non-limiting examples of such agents caninclude a viral infection with a DNA integrating virus (e.g.,adeno-associated virus, retrovirus, human T-lymphotropic virus, HIV-1,oncovirus, hepatitis virus, hepatitis B virus); DNA damaging chemicals(e.g., acetaldehyde, polycyclic aromatic hydrocarbons, benzenes,nitrosamines, tobacco smoke, aflatoxin, and the like); DNA damagingchemotherapeutic agents (e.g., bleomycin, mitomycin, nitrogen mustards(e.g., mechlorethamine, cyclophosphamide, melphalan, chlorambucil,ifosfamide and busulfan), nitrosoureas (e.g., N-Nitroso-N-methylurea(MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU),fotemustine and streptozotocin), tetrazines (e.g., dacarbazine,mitozolomide and temozolomide),aziridines (e.g., thiotepa, mytomycin anddiaziquone (AZQ)), cisplatins (e.g., cisplatin, carboplatin andoxaliplatin) procarbazine and hexamethylmelamine); and ionizing orultraviolet radiation. Exposure to such agents can be the result of anaccident, infection and/or environmental exposure or the result of atherapeutic administration of such agents.

In some embodiments, the increased level of DNA damage can be occurringin a cell type affected by the cancer, autoimmune disease,immunodeficiency, and/or neurodegenerative disease. In some embodiments,the subject is determined to have an increased level of DNA damageoccurring in a cell selected from the group consisting of: a cancercell; an immune system cell; or a nervous system cell.

In some embodiments, the DNA editing enzyme can be AID. In someembodiments, the level of AID can be the level of AID in a blood cell.In some embodiments, the level of AID can be the level of AID in a Bcell.

In some embodiments, an increased level of AID can be a detectable levelof AID, e.g., as described below herein.

In some embodiments, the subject can be a human subject.

In some embodiments, methods provided herein treat cancers and/orautoimmune disorders by inhibiting DNA double strand break repair. Thisinhibition proves lethal to cells expressing AID, as AID generateswidespread genomic breaks, and the treatment with a double strand breakrepair inhibitor prevents the repair of these lesions which are beinggenerated by the cell itself. This results in cell death in the subjectwhich is specific to the cells expressing AID, e.g., cancerous B cellsand/or autoimmune cells. Accordingly, as described herein, In someembodiments there is a provided a treatment paradigm that selectivelyinduces self-destruction of certain diseased cells, while reducing theunintended side effects in healthy tissues.

In some embodiments, methods of detecting cancers in patients withincreased levels of DNA damage or increased levels of DNA editingenzymes are disclosed in WO2016/094897, incorporated herein byreference.

In some embodiments, the cancer to be treated is a type with highexpression of a DNA editing enzyme. In some embodiments, the cancer tobe treated is a B-cell neoplasm.

Another embodiment is a method of treating a cancer by administering tothe subject an effective amount of one or more disclosed compounds, or apharmaceutically acceptable salt or solvate thereof, or thecorresponding pharmaceutical composition. In one aspect, the cancer isselected from the group consisting of lymphoma, leukemia, and a plasmacell neoplasm. In another aspect, the cancer selected from the groupconsisting of carcinoma and sarcoma.

In some embodiments, the cancer to be treated is a lymphoma. Lymphomaswhich can be treated by the disclosed methods include Non-Hodgkin'slymphoma; Burkitt's lymphoma; small lymphocytic lymphoma;lymphoplasmacytic lymphoma; MALT lymphoma; follicular lymphoma; diffuselarge B-cell lymphoma; mantle cell lymphoma; and T-cell lymphoma.

Lymphoma is a malignancy in the lymphatic cells of the immune system(e.g., B cells, T cells, or natural killer (NK) cells). Lymphomas oftenoriginate in the lymph nodes and present as solid tumors. They canmetastasize to other organs such as the brain, bone, or skin. Extranodalsites are often located in the abdomen. Lymphomas are closely related tothe lymphoid leukemia and in some cases a particular form of cancer iscategorized as both a lymphoma and a leukemia.

Leukemias which can be treated by the disclosed methods include acutelymphoblastic leukemia (ALL); Burkitt's leukemia; B-cell leukemia;B-cell acute lymphoblastic leukemia; chronic lymphocytic leukemia (CLL);acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML);and T-cell acute lymphoblastic leukemia (T-ALL).

In some embodiments, the cancer to be treated is B-cell neoplasms,B-cell leukemia, B-cell acute lymphoblastic leukemia, chroniclymphocytic leukemia, chronic myelogenous leukemia, Burkitt's leukemia,acute myelogenous leukemia and/or T-ALL. The maturation of B cells mosttypically ceases or substantially decreases when the foreign antigen hasbeen neutralized. Occasionally, however, proliferation of a particular Bcell will continue unabated; such proliferation can result in a cancerreferred to as “B-cell lymphoma” or a “B-cell leukemia.” In someembodiments the cancer to be treated is chronic lymphocytic leukemia(CLL) or chronic myelogenous leukemia (CML).

In some embodiments, the cancer to be treated is a plasma cell neoplasm.Examples for plasma cell neoplasms include multiple myeloma; plasma cellmyeloma; plasma cell leukemia and plasmacytoma.

Carcinomas which can be treated by the disclosed methods include coloncancer; liver cancer; gastric cancer; intestinal cancer; esophagealcancer; breast cancer; ovarian cancer; head and neck cancer; lungcancer; and thyroid cancer.

Sarcomas which can be treated by the disclosed methods include softtissue sarcoma and bone sarcoma.

Any cancer characterized by high levels of DNA damage and/or DNA editingenzyme expression can be treated with a compound as described herein,e.g., a compound of the present application. For example, sarcomas,epithelial cell cancer (carcinomas), colon cancer, gastric cancer,intestinal cancer, liver cancer, hepatocellular cancer, breast cancer,thyroid cancer, esophageal cancer, lung cancer, brain cancer, head andneck cancer, melanoma, renal cancer, prostate cancer, hemangioma,rhabdomyosarcoma, chondrosarcoma, osteosarcoma, fibrosarcoma andcholangiocarcinoma may be characterized by high levels of a DNA editingenzyme expression, e.g., AID. In some embodiments the cancer to betreated is colon cancer, liver cancer, gastric cancer, intestinalcancer, breast cancer, lung cancer, thyroid cancer and/orcholangiocarcinoma.

In some embodiments, cancers that can be treated by the disclosedmethods include cancer of the bladder, blood, bone, bone marrow, brain,breast, colon, esophagus, gastrointestine, gum, head, kidney, liver,lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue,or uterus. In addition, the cancer may specifically be of the followinghistological type, though it is not limited to these: neoplasm,malignant; carcinoma; carcinoma, undifferentiated; giant and spindlecell carcinoma; sarcomas; small cell carcinoma; papillary carcinoma;squamous cell carcinoma; lymphoepithelial carcinoma; basal cellcarcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillarytransitional cell carcinoma; adenocarcinoma; gastrinoma, malignant;cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellularcarcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoidcystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma,familial polyposis coli; solid carcinoma; carcinoid tumor, malignant;branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma;chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma;basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma;follicular adenocarcinoma; papillary and follicular adenocarcinoma;nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma;endometroid carcinoma; skin appendage carcinoma; apocrineadenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma;mucoepidermoid carcinoma; cystadenocarcinoma; papillarycystadenocarcinoma; papillary serous cystadenocarcinoma; mucinouscystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma;infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma;inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma;adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma,malignant; ovarian stromal tumor, malignant; thecoma, malignant;granulosa cell tumor, malignant; androblastoma, malignant; sertoli cellcarcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant;paraganglioma, malignant; extra-mammary paraganglioma, malignant;pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanoticmelanoma; superficial spreading melanoma; malig melanoma in giantpigmented nevus; epithelioid cell melanoma; blue nevus, malignant;sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma;liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonalrhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixedtumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma;carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant;phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant;dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii,malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma;hemangioendothelioma, malignant; Kaposi's sarcoma; hemangiopericytoma,malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma;chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma;giant cell tumor of bone; Ewing's sarcoma; odontogenic tumor, malignant;ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblasticfibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant;ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillaryastrocytoma; astroblastoma; glioblastoma; oligodendroglioma;oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma;ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactoryneurogenic tumor; meningioma, malignant; neurofibrosarcoma;neurilemmoma, malignant; granular cell tumor, malignant; malignantlymphoma; Hodgkin's disease; hodgkin's; paragranuloma; malignantlymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse;malignant lymphoma, follicular; mycosis fungoides; other specifiednon-Hodgkin's lymphomas; malignant histiocytosis; multiple myeloma; mastcell sarcoma; immunoproliferative small intestinal disease; leukemia;lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcomacell leukemia; myeloid leukemia; basophilic leukemia; eosinophilicleukemia; monocytic leukemia; mast cell leukemia; megakaryoblasticleukemia; myeloid sarcoma; and hairy cell leukemia.

In some embodiments, for the disclosed method, the cancer ischaracterized by mutations in the mutS homologues (e.g., MSH2, MSH3, andMSH6), mutL homologues (e.g., MLH1), or mismatch repair endonucleasePMS2. Mutations are changes in the genetic code. They include pointmutations and frameshift mutations. In a point mutation, one nucleotideis swapped out for another. Therefore, the mutation occurs at a singlepoint or location within the DNA strand. Frameshift mutations are due toeither insertions or deletions of nucleotides. This causes the entireDNA strand to elongate or to shrink in size. Thus, frameshift mutationsmay alter all of the codons that occur after the deletion or insertion.The mutations referred to herein include, but are not limited to,insertions, deletions, duplications, inversions, or other recognizedpoint mutations. It has now been found that RAD51 inhibitors areparticularly effective in treating cancers with mutations in MSH (e.g.,MSH6), MLH, or PMS2.

MutS Homolog 2 (MSH2) is a protein that in humans is encoded by the MSH2gene, which is located on chromosome 2. MSH2 is a tumor suppressor geneand more specifically a caretaker gene that codes for a DNA mismatchrepair (MMR) protein, MSH2, which forms a heterodimer with MSH6 to makethe human MutSa mismatch repair complex. It also dimerizes with MSH3 toform the MutSI3 DNA repair complex. MSH2 is involved in many differentforms of DNA repair, including transcription-coupled repair, homologousrecombination, and base excision repair. Examples of the mutations inMSH2 include, but are not limited to, g.47630253_47630254del,g.47702411_47702421del, g.47709913_47709915inv, g.47635629_47635634del,g.47637227_47637236dup, g.47639550_47639561del,g.(?_47630206)_(47710367_?)del, g.(?_47630206)_(47643569_47656880)del,g.47630263_47643568del, g.(?_47630206)_(47657081_47672686)del,g.47630263_47657080del, g.(?_47630206)_(47672797_47690169)del,g.47630263_47672796del, g.(?_47630206)_(47672797_47690169)del,g.(?_47630206)_(47693948_47698103)del, g.47630263_47693947del,g.(?_47630206)_(47698202_47702163)del,g.(?_47630206)_(47630542_47635539)del,g.(?_47630206)_(47708011_47709917)del,g.(?_47630206)_(47635695_47637232)del,g.(?_47630206)_(47635695_47637232)del,g.(?_47630206)_(47637512_47639552)del,g.(?_47630206)_(47639700_47641407)del,g.(?_47630206)_(47641558_47643434)del, g.47618487_47650860delins(155),g.47628578_47638433del, g.47595033_47662777del, g.47583175_47667707de,g.47625602_47636880del, g.47554933_47699909del, g.47629508_47649552del,g.47629375_47651274del, g.(?_47630206)_(47630542_47635539)del,g.(?_47630206)_(47635695_47637232)del, g.47643509_47643510del,g.47643529_47643530dup, g.47656746_47657199dup, g.47656661_47663325del,g.(47643569_47656880)_(47710367_?)del,g.(47643569_47656880)_(47710367_?)del, g.47656881_47657080del,g.(47643569_47656880)_(47657081_47672686)del,g.(47643569_47656880)_(47657081_47672686)del,g.(47643569_47656880)_(47657081_47672686)del,g.(47643569_47656880)_(47657081_47672686)dup,g.(47643569_47656880)_(47657081_47672686)dup,g.(47643569_47656880)_(47672797_47690169)del,g.(47643569_47656880)_(47693948_47698103)del, g.47656881_47693947del,g.(47643569_47656880)_(47702410_47703505)del,g.47656881_47656882ins(173), g.47656901_47656902insA, g.47656903del,g.47656912del, g.47630440del, g.47656923del, g.47656931_47656932dup,g.47656943del, g.47656943_47656949delinsCCCAGA, g.47656948dup,g.47656996dup, g.47657000_47657001dup, g.47630449del, g.47657007dup,g.47657008del, g.47657020_47657023dup, g.47657025_47657026del,g.47657026dup, g.47657030_47657031del, g.47657047_47657050del,g.47657053del, g.47657053_47657057del, g.47657064del, g.47657073dup,g.47657312_47676594del, g.47668611_47674615del, g.47672116_47675123del,g.47666463_47677632del, g.47666403_47677572del,g.(47657081_47672686)_(47710367_?)del,g.(47657081_47672686)_(47710367_?)inv,g.47671507_47675022delinsCATTCTCTTTGAAAA, g.47657278_47676557del,g.47672687_47672796del, g.(47657081_47672686)_(47672797_47690169)del,g.(47657081_47672686)_(47672797_47690169)del,g.(47657081_47672686)_(47693948_47698103)del,g.(47657081_47672686)_(47698202_47702163)del,g.(47657081_47672686)_(47708011_47709917)del, g.47672691dup,g.47672697dup, g.47672721_47672744delins47672748_47672771inv,g.47672728_47672729del, g.47672731dup, g.47672750_47672751insGG,g.47672755_47672758del, g.47672762_47672763del, g.47630466_47630494del,g.47686194_47697740del, g.(47672797_47690169)_(47710367_?)del,g.(47672797_47690169)_(47690294_47693796)del,g.(47672797_47690169)_(47693948_47698103)del, g.47690170_47693947del,g.(47672797_47690169)_(47693948_47698103)del,g.(47672797_47690169)_(47693948_47698103)dup,g.(47672797_47690169)_(47705659_47707834)del, g.47690173del,g.47690191del, g.47690216_47690217dup, g.47690227del, g.47690227dup,g.47690228_47690232del, g.47690230_47690231del, g.47690240del,g.47690240_47690243del, g.47630475del, g.47630475_47630476del,g.47690259_47690260delinsCT, g.47690277dup, g.47690280del,g.47690283dup, g.(47690294_47693796)_(47702410_47703505)del,g.47630484_47630485insG, g.47693838_47693839del, g.47693862del,g.47693864del, g.47693873del, g.47693880dup, g.47693913del,g.47693924_47693925dup, g.47630493del, g.47697730_47706125del,g.(47693948_47698103)_(47710367_?)del,g.(47693948_47698103)_(47698202_47702163)del,g.(47693948_47698103)_(47705659_47707834)del, g.47698107del,g.47698109del, g.47698109_47698110insA, g.47630496del, g.47698118del,g.47698125del, g.47698129dup, g.47698138_47698139del,g.47698142_47698146del, g.47698144dup, g.47698147_47698148del,g.47698147_47698148dup, g.47698147_47698148insT, g.47698159del,g.47698162del, g.47698506_47703472del, g.47701803_47708848del,g.(47698202_47702163)_(47710367_?)del,g.(47698202_47702163)_(47702410_47703505)del,g.(47698202_47702163)_(47703711_47705410)del,g.(47698202_47702163)_(47705659_47707834)del, g.47702164del,g.47702175_47702176insA, g.47702183_47702186del,g.47702185_47702186insCT, g.47702190_47702192del, g.47702191dup,g.47702192_47702193del, g.47702213del, g.47702231del, g.47702242dup,g.47702257del, g.47702262_47702263dup, g.47630516_47630517dup,g.47630517del, g.47630517dup, g.47702289_47702290inv,g.47702293_47702296del, g.47702301dup, g.47702315del, g.47702315del,g.47702328_47702329del, g.47630522dup, g.47702339del,g.47702371_47702374dup, g.47702384_47702385del, g.47702386_47702389del,g.47702388del, g.47702388_47702389del, g.47702390del,g.47702390_47702391del, g.47702400_47702401del, g.47703506_47703710del,g.47703506_47708010del, g.47703510del, g.47703515del,g.47703521_47703522del, g.47703535_47703536del, g.47703546_47703547del,g.47703548_47703611dup, g.47630534del, g.47703571dup,g.47703574_47703581del, g.47703585dup, g.47630350del,g.47632107_47668733del, g.47703613del,g.(47630542_47635539)_(47643569_47656880)del,g.(47630542_47635539)_(47643569_47656880)inv,g.(47630542_47635539)_(47657081_47672686)del, g.47635540_47657080del,g.(47630542_47635539)_(47672797_47690169)del,g.(47630542_47635539)_(47690294_47693796)del,g.(47630542_47635539)_(47705659_47707834)del, g.47635540_47635694del,g.(47630542_47635539)_(47635695_47637232)del,g.(47630542_47635539)_(47635695_47637232)del,g.(47630542_47635539)_(47637512_47639552)del, g.47703635dup,g.47703641dup, g.47635542_47635549del, g.47703660_47703663del,g.47703667dup, g.47630351dup, g.47703704del, g.47703826_47707938del,g.(47703711_47705410)_(47705659_47707834)del, g.47705428_47705431del,g.47705437_47705438insA, g.47635551_47635552del, g.47705440_47705441del,g.47705461del, g.47705490del, g.47705494del, g.47705495del,g.47635557_47635558del, g.47705505del, g.47705535dup, g.47705547del,g.47705560_47705561dup, g.47705561dup, g.47705562dup, g.47705588del,g.47705608_47705609del, g.47705618dup, g.47705627dup,g.47635571_47635601delins(217), g.(47705659_47707834)_(47710367_?)del,g.(47705659_47707834)_(47708011_047709917)del, g.47707842_47707843del,g.47707861del, g.47707861_47707874dup, g.47707878_47707884del,g.47707878_47707884del, g.47707883del, g.47707895_47707905del,g.47707897del, g.47707901_47707902del, g.47707905_47707906del,g.47707921del, g.47635583dup, g.47635583_47635584del,g.47707969_47707973del, g.47707996_47707997ins(115),g.47708009_47708010del, g.(47708011_47709917)_(47710367_?)del,g.47635591_47635592del, g.47635597_47635618dup, g.47635606_47635607del,g.47630359dup, g.47635672del, g.47635675_47635678del, g.47630364dup,g.47635680dup, g.47636862_47639040del, g.47636781_47638831del,g.47636753_47638155del, g.47636552_47638597del,g.(47635695_47637232)_(47643569_47656880)del,g.(47635695_47637232)_(47643569_47656880)del,g.(47635695_47637232)_(47657081_47672686)del,g.(47635695_47637232)_(47672797_47690169)del,g.(47635695_47637232)_(47698202_47702163)del,g.(47635695_47637232)_(47637512_47639552)del,g.(47635695_47637232)_(47641558_47643434)del, g.47637234del,g.47637246_47637247del, g.47637253_47637254del, g.47637254_47637255del,g.47637254_47637255del, g.47637265del, g.47637274del, g.47637282del,g.47637320del, g.47637372_47637375del, g.47637377_47637449dup,g.47637379del, g.47637384del, g.47637394_47637395del,g.47637396_47637397del, g.47637417del, g.47637427_47637435del,g.47637437_47637439del, g.47637453del, g.47637458dup,g.47637479_47637482dup, g.47637482dup, g.47637504_47637505del,g.47637508_47637511del, g.47638050_47653430del, g.47638302_47648462del,g.47638478_47648643del, g.(47637512_47639552)_(47710367_?)del,g.(47637512_47639552)_(47643569_47656880)del, g.47639553_47643568del,g.(47637512_47639552)_(47657081_47672686)del,g.(47637512_47639552)_(47657081_47672686)del,g.(47637512_47639552)_(47672797_47690169)del,g.(47637512_47639552)_(47639700_47641407)del,g.(47637512_47639552)_(47641558_47643434)del, g.47639557_47639561del,g.47639582_47639586delinsTAAT, g.47639583_47639584del, g.47639594del,g.47639594dup, g.47639598del, g.47639603_47639604del,g.47639611_47639612del, g.47639612del, g.47639618_47639621del,g.47639624_47639628delinsTTA, g.47630401dup, g.47639632dup,g.47639638_47639641dup, g.47639638_47639641dup, g.47639639del,g.47639639del, g.47639642dup, g.47630403_47630404insC, g.47639653del,g.47639666del, g.47639666_47639669del, g.47639668del,g.47639670_47639673delinsTT, g.47639674_47639675dup,g.47639695_47639696del, g.47639707_47642985del, g.47641402_47642007del,g.(47639700_47641407)_(47643569_47656880)del, g.47641408_47643568del,g.(47639700_47641407)_(47657081_47672686)del,g.(47639700_47641407)_(47672797_47690169)del,g.(47639700_47641407)_(47641558_47643434)del,g.(47639700_47641407)_(47641558_47643434)del, g.47641410del,g.47641425_47641426del, g.47641426_47641429del, g.47630412del,g.47641451del, g.47641454dup, g.47641455dup, g.47641469del,g.47641478del, g.47641488_47641491del, g.47641496_47641497del,g.47641503del, g.47641513_47641514dup, g.47641530_47641537dup,g.47642509_47655432del, g.(47641558_47643434)_(47643569_47656880)del,g.(47641558_47643434)_(47693948_47698103)del, g.47630424_47630433del,g.47643450dup, g.47643462_47643463del, g.47643462_47643463ins(4),g.47643464_47643465insNC_000022.10:3578816935788352, g.47643465dup.

MutS Homolog 3 (MSH3) is a human homologue of the bacterial mismatchrepair protein MutS that participates in the mismatch repair (MMR)system. MSH3 typically forms the heterodimer MutSβ with MSH2 in order tocorrect long insertion/deletion loops and base-base mispairs inmicrosatellites during DNA synthesis. Deficient capacity for MMR isfound in approximately 15% of colorectal cancers, and somatic mutationsin the MSH3 gene can be found in nearly 50% of MMR-deficient colorectalcancers. Examples of the mutations in MSH3 include, but are not limitedto, g.79970809de1.

MSH6 encodes MutS homologue 6 (MSH6), a member of the Mutator S (MutS)family of proteins that are involved in DNA mismatch repair (MMR). TheMSH6 protein forms a heterodimer with MutS homologue 2 (MSH2) in bothhuman and yeast. Human MSH2/6 recognizes single base-base mismatches andshort insertion/deletion loops. Upon recognition of a mismatch, MSH2/6complex binds and exchanges ADP for ATP, resulting in a conformationalchange to the complex that precedes base pair dissolution, baseexcision, and repair.

MSH6 mutations include frameshift and/or nonsense mutations and canresult in non-functional MSH6 and loss of protein expression. Examplesinclude a frameshift mutation at MSH6 amino acid residue 290 and acompounding missense T1189I.

Inactivating MSH6 mutations can be detected in cancers by routinediagnostics methods. These methods include, but are not limited to,obtaining cancer cells and other diagnostic indicators such asperipheral blood mononuclear cells (PBMCs), PBMC subpopulations,circulating blasts (CD34+ cells), circulating tumor cells andcirculating exosomescancer cells by biopsy and blood tests and byobtaining lymphatic or other bodily fluids. It is then determined fromthe cancer cells or other diagnostic indicators whether the cancerexhibits an inactivating MSH6 mutation is by methodology known in theart, for example, direct DNA sequencing and multiplex ligation dependentprobe amplification, RNA sequencing (RNA-Seq), microarray, quantitativePCR, or NanoString™ gene expression panels, or MSH6 protein byimmunohistochemistry, flow cytometry, immunocytochemistry or Westernblot. Methods for identifying inactivating MSH6 mutations are disclosedin Houlleberghs H, Goverde A, Lusseveld J, Dekker M, Bruno M J, et al.(2017) Suspected Lynch syndrome associated MSH6 variants: A functionalassay to determine their pathogenicity. PLOS Genetics 13(5): e1006765.https://doi.org/10.1371/j ournal.pgen.1006765.

Examples of the mutations in MSH6 include, but are not limited to,g.48032846_48032849del, g.48032846_48032849del, g.48032846_48032849del,g.48033337_48033342del, g.48033420_48033422del,g.(?_48010221)_(48034092)del, g.(?_48010221)_(48018263_48023032)del,g.47998510_48020183del, g.48007276_48020272del, g.48026207del,g.48026223del, g.48026223del, g.48026257_48026261del,g.48026261_48026265del, g.48026312_48026313del, g.48026398del,g.48026543_48026544dup, g.48026693dup, g.48026702del, g.48026712del,g.48026718dup, g.48026736_48026737delinsAG, g.48026736_48026737delinsG,g.48026750_48026751del, g.48026754_48026757del, g.48026756_48026759del,g.48026759_48026760del, g.48026906del, g.48026928_48026931del,g.48026941dup, g.48026991del, g.48027023_48027024del, g.48027079del,g.48027079_48027082dup, g.48027167_48027168del, g.48027172_48027173dup,g.48027178_48027185del, g.48027184_48027185del, g.48027272_48027275del,g.48027470_48027471del, g.48027501_48027502del,g.48027501_48027502delTG, g.48027657dup, g.48027691_48027694del,g.48027733_48027736dup, g.48027794_48027796delinsC,g.48027841_48027842del, g.48027887del, g.48027890dup,g.48027973_48027980del, g.48028067del, g.48028098del, g.48028106del,g.48028175_48028176del, g.48028241_48028242del,g.48028241_48028242delTT, g.48028272_48028284dup,g.48028277_48028278del, g.48030558_48030559del, g.48030126_48032394del,g.48030568del, g.48030581_48030584del, g.48030584_48030585dup,g.48030607del, g.48030645_48030646insT, g.48030647del, g.48030647dup,g.48030649dup, g.48030654_48030660del, g.48030659dup,g.48030697_48030698del, g.48030698del, g.48030706del, g.48030710dup,g.48030727_48030728insC, g.48030765_48030829del,c.3438+797_3438+798insTATins1839_3439−428,c.3438+797_3438+798insTATins1839_3439−428, g.48032121_48032122del,g.48032123_48032124del, g.48032124dup, g.48032126_48032129del,g.48032129_48032130insA, g.48032129_48032132dup,g.(48032167_48032756)_(48034092_?)del, g.48032809_48032812del,g.48032835dup, g.48032846_48032849del, g.48033374_48033402dup,g.48033395_48033398del, g.48033421_48033433del, g.48033425_48033428dup,g.48033453_48033454insA, g.48033494_48033523del, g.48033495_48033496del,g.48033593dup, g.48033610_48033613dup, g.48033629_48033635del,g.48033636_48033639dup, g.48033676_48033682del, g.48033707dup,g.48033709_48033716dup, g.48033721_48033724dup, g.48033727_48033730dup,g.48033728_48033746dup,g.(48033742_48033743)_(48033742_48033743)ins(32), g.48033746dup,g.48033748_48033751del, g.48033758_48033768del,g.48033773_48033774insATCA, g.48033773_48033776dup,g.48033785_48033789dup, g.48033887_48033910inv,g.(48018263_48023032)_(48032167_48032756)del,g.(48018263_48023032)_(48023203_48025749)del, g.48023097_48023098del,g.48025773dup, g.48025832del, g.48025860_48025861insT,g.48025884_48025885del, g.48025967dup.

MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) is a proteinthat in humans is encoded by the MLH1 gene located on Chromosome 3. Itis a gene commonly associated with hereditary nonpolyposis colorectalcancer.

Examples of the mutations in MSH6 include, but are not limited to,g.37089113_37089115del, g.37089175del, g.37090379_37090393del,g.37038201_37038202del, g.37042531_37042542del, g.37053339_37053355del,g.37053354del, g.37053590_37053591insT, g.37034841_37092337del,g.(?_37034841)_(37092337_?)del, g.(?_37034841)_(37061955_37067127)del,g.(?_37034841)_(37035155_37038109)del,g.(?_37034841)_(37035155_37038109)del,g.(?_37034841)_(37070424_37081676)del,g.(?_37034841)_(37083823_37089009)del, g.37034841_37083822del,g.(?_37034841)_(37038201_37042445)del,g.(?_37034841)_(37042545_37045891)del, g.37034841_37042544del,g.(?_37034841)_(37042545_37045891)del,g.(?_37034841)_(37042545_37045891)del,g.(?_37034841)_(37045966_37048481)del,g.(?_37034841)_(37050397_37053310)del,g.(?_37034841)_(37059091_37061800)del, g.37034658_37038806del,g.36961079_37138741del, g.37061923del, g.37061927del, g.37061933del,g.37061939del, g.37061942dup, g.37035140_37035141del, g.37070417del,g.37070417_37070418insT, g.37070419dup, g.37070422_37070423insT,g.37080355_37083368del, g.(37070424_37081676)_(37092337_?)del,g.(37070424_37081676)_(37081786_37083758)del,g.(37070424_37081676)_(37083823_37089009)del, g.37038148_37038151del,g.37038149del, g.37038149dup, g.37081690_37081691del,g.37081691_37081692del, g.37081706_37081708del, g.37081710_37081711del,g.37035053_37035066del, g.37038154del, g.37038154_37038157del,g.37081738_37081739del, g.37081740del, g.37081753dup,g.37081757_37081761dup, g.37081782_37081783insAAGT,g.37081787_37081793delinsATTT,g.(37081786_37083758)_(37083823_37089009)del,g.(37081786_37083758)_(37089175_37090007)del, g.37083759del,g.37083780dup, g.37083781_37083784del, g.37083781_37083784delCTCA,g.37083808_37083809del, g.37083816del, g.37086069_37089606del,g.37084092_37089247del, g.37084590_37089786del,g.(37083823_37089009)_(37092337_?)del,g.(37083823_37089009)_(37089175_37090007)del, g.37089010_37089174del,g.(37083823_37089009)_(37090509_37091976)del, g.37089023del,g.37089026_37089027del, g.37089027del, g.37089036del, g.37089036dup,g.37038168dup, g.37089042del, g.37089047del, g. 37089050_37089053del, g.37089056_37089057del, g.37089061_37089062del, g.37089078_37089096del,g.37089090dup, g.37089099dup, g.37089107_37089110dup,g.37089109_37089110del, g.37089130_37089132del,g.37089130_37089132delAAG, g.37089131delinsTTCTT, g.37089133del,g.37089133delG, g.37089144del, g.37089155del, g.37089155_37089161del,g.37089158_37089161del, g.37089162_37089166del, g.37089171del,g.(37089175_37090007)_(37090101_37090394)del, g.37035056_37035072del,g.37090013del, g.37090015dup, g.37038183_37038184del,g.37090024_37090037dup, g.37090025_37090053dup, g.37090027dup,g.37038184dup, g.37090031_37090032insT, g.37090041del, g.37090057del,g.37090064_37090067del, g.37038188del, g.37090082del,g.37090086_37090087del, g.37090087_37090088del,g.37090097_37090101delinsC, g.37090099del, g.37038191dup,g.(37090101_37090394)_(37092337_?)del, g.37035057_37035073del,g.37090405dup, g.37090411_37090415del, g.37090414del, g.37038194del,g.37038198del, g.37090472_37090478del, g.37039445_37059613dup,g.37039760_37052440del, g.37090481_37090482del, g.37090483_37090484del,g.37090483_37092045del, g.37040732_37043185delinsACATAGTA,g.37042445_37042446del, g.(37038201_37042445)_(37042545_37045891)del,g.(37038201_37042445)_(37048555_37050304)del,g.(37038201_37042445)_(37050397_37053310)del,g.(37038201_37042445)_(37053591_37055922)del, g.37090497_37090498del,g.37090497_37090498delTC, g.37090504_37090507del,g.(37090509_37091976)_(37092337_?)del,g.(37090509_37091976)_(37092337_?)dup, g.37091977_37091978del,g.37091978_37091987del, g.37042448_37042451del, g.37091984_37091990del,g.37042451_37042453del, g.37092020_37092021del, g.37092022_37092068dup,g.37092027_37092028del, g.37092027_37092028dup, g.37092030dup,g.37092052_37092055del, g.37092054_37092055del, g.37092068_37092071dup,g.37092091dup, g.37092094_37092097delins(30), g.37092096_37092106del,g.37092097del, g.37092125_37092126delAA, g.37092125_37092126del,g.37092139_37092142dup, g.37092142dup, g.37035060dup,g.37042469_37042470del, g.37042470del, g.37042482dup, g.37042485del,g.37042499del, g.37042546dup, g.37044472_37046589del,g.37045648_37049941del, g.37045095_37054651del, g.37045072_37046861del,g.(37042545_37045891)_(37045966_37048481)del,g.(37042545_37045891)_(37092337_?)del,g.(37042545_37045891)_(37048555_37050304)del,g.(37042545_37045891)_(37050397_37053310)del, g.37045892_37050396del,g.37035069del, g.37045926del, g.37045931del, g.37045939_37045940dup,g.37045957_37045958del, g.37045963del, g.37035075del,g.37048067_37049287del, g.(37045966_37048481)_(37048555_37050304)del,g.(37045966_37048481)_(37050397_37053310)del, g.37048483del,g.37048483_37048503delinsT, g.37048486_37048487delinsGTT, g.37048489del,g.37048490del, g. 37035076_37035077insCCCA, g.37035077_37035078dup,g.37048505_37048508del, g.37048521del, g.37048529dup, g.37035082dup,g.37049873_37052281del, g.37049839_37052249del, g.37049800_37052209del,g.37049640_37050445del, g.37050305_37050396del,g.(37048555_37050304)_(37050397_37053310)del, g.37050305_37050396del,g.37050319_37050320del, g.37050339del, g.37050348del,g.37050353_37050354del, g.37050354dup, g.37050364del,g.37050375_37050376insGA, g.37035090del, g.37050382_37050383delinsAT,g.37050382_37050383delinsCT, g.37050390_37050396del,g.37052950_37060990del, g.(37050397_37053310)_(37067499_37070274)dup,g.(37050397_37053310)_(37053591_37055922)del,g.(37050397_37053310)_(37056036_37058996)del, g.37053353del,g.37053510_37053511del, g.37035099del, g.37053545_37053546insT,g.37053562del, g.37053578del, g.37053578dup, g.37053585del,g.37053586_37053589del, g.37053591del, g.37053590_37053591delinsAT,g.37055920_37055921del, g.37055914_37055938del,g.(37053591_37055922)_(37070424_37081676)del,g.(37053591_37055922)_(37083823_37089009)del,g.(37053591_37055922)_(37059091_37061800)del, g.37035105del,g.37055928dup, g.37035106_37035116del, g.37055938del, g.37035108del,g.37055972_37055975del, g.37055976_37055979del, g.37035111del,g.37055990dup, g.37035114del, g.37035116del, g.37056036del,g.37056037dup, g.37058993_37059001del,g.(37056036_37058996)_(37070424_37081676)del,g.(37056036_37058996)_(37059091_37061800)del, g.37058997_37059000del,g.37059014_37059017del, g.37059017_37059021del, g.37059027_37059030dup,g.37035122del, g. 37059062_37059063insT, g.37059065_37059066del,g.37059066del, g.37059066dup, g.37059072_37059073del,g.37059072_37059073dup, g.37059090_37059093del, g.37061595_37061913del,g.37061308_37066756del, g.37061207_37063077del, g.(37059091_37061800)(37092337_?)del, g.(37059091_37061800)_(37061955_37067127)del,g.37061801_37061954del, g.(37059091_37061800)_(37083823_37089009)del,g.37061803dup, g.37061804del, g.37061817del, g.37061837_37061838dup,g.37061844del, g.37061851dup, g.37061855dup, g.37061870del,g.37061904_37061906del, g.37061910del, g.37035047del, g.[37049179_37051317delinsTG; 37051667_37054327delinsCA].

Human PMS2 related genes are located at bands 7p12, 7p13, 7q11, and7q22. Exons 1 through 5 of these homologues share high degree ofidentity to human PMS2. The product of this gene is involved in DNAmismatch repair. The protein forms a heterodimer with MLH1 and thiscomplex interacts with MSH2 bound to mismatched bases. Defects in thisgene are associated with hereditary nonpolyposis colorectal cancer, withTurcot syndrome, and are a cause of supratentorial primitiveneuroectodermal tumors.

Examples of the mutations in PMS2 include, but are not limited to,g.(?_6012870)_(6048737_?)del, g.6012870_6048737del,g.(6027252_6029430)_(6048737_?)del, g.(6045663_6048627)_(6048737_?)del,g.6029554del, g.6029499dup, g.6029495_6029496del,g.6029462_6029463delinsTAAA, g.5992485_6028601del,g.(6018328_6022454)_(6027252_6029430)del,g.(6013174_6017218)_(6027252_6029430)del, g.6027226_6027227ins(20),g.6027175del, g.6027090dup, g.6036705_6044207delinsCG, g.6026666dup,g.6026628del, g.6043671del, g.6026565dup, g.6026565dupT,g.6018315_6018316del, g.6018306_6018310del, g.6018306_6018310delAGTTA,g.6043633_6043634dup, g.6018256_6018259del, g.6015623_6017501del,g.6016429_6017479del, g.6017300_6017303del, g.6045579_6045674delinsATTT,g.(6043690_6045522)_(6045663_6048627)del,g.(?_6012870)_(6042268_6043320)del,g.(6035265_6036956)_(6042268_6043320)del, g.6038283_6039384del,g.6038901del, g.6038851dup, g.(6035265_6036956)_(6037055_6038738)del,g.6037019_6037024delinsCTTCACACACA, g.6036980del, g.6036958dup,g.6035323_6035324insJN866832.1,g.(6022623_6026389)_(6035265_6036956)del,g.(6031689_6035164)_(6035265_6036956)del, g.6035204_6035207del,g.6035205_6035206del, g.(?_6012870)_(6031689_6035164)del,g.(6027252_6029430)_(6031689_6035164)del,g.(6029587_6031603)_(6031689_6035164)del, g.6028725_6029882del,g.(?_6012870)_(6029587_6031603)del.

The present application provides a method of treating patients withLynch syndrome to reduce the likelihood of developing or treatingcancers derived from Lynch syndrome patients, by administering to thesubject an effective amount of one or more disclosed compounds, or apharmaceutically acceptable salt or solvate thereof, or thecorresponding pharmaceutical composition.

Lynch syndrome is a hereditary disorder caused by a mutation in amismatch repair gene in which affected individuals have a higher thannormal chance of developing colorectal cancer, endometrial cancer, andvarious other types of aggressive cancers, often at a young age—alsocalled hereditary nonpolyposis colon cancer (HNPCC).

The mutations of specific mismatch repair (MMR) genes including but notlimited to MLH1, MSH2, MSH6, PMS2, and EPCAM-TACSTD1 deletions areresponsible for Lynch syndrome. These genes work in repairing mistakesmade when DNA is copied in preparation for cell division. The defects inthe genes disallow repair of DNA mistakes and as cells divide, errorsstack and uncontrollable cell growth may result in cancer.

Those with Lynch syndrome carry up to an 85% risk of contracting coloncancer as well as a higher than average risk for endometrial cancer,stomach cancer, pancreatic cancer, kidney/ureter tract cancer,hepatobiliary tract cancer, gastric tract cancer, prostate cancer,ovarian cancer, gallbladder duct cancer, brain cancer, small intestinecancer, breast cancer, and skin cancer.

In some embodiments for the disclosed method, the method is a method oftreating cancer derived from Lynch syndrome, selected from the groupconsisting of colon cancer, endometrial cancer, stomach cancer,pancreatic cancer, kidney/ureter tract cancer, hepatobiliary tractcancer, gastric tract cancer, prostate cancer, ovarian cancer,gallbladder duct cancer, brain cancer, small intestine cancer, breastcancer, and skin cancer.

In some embodiments, the method is a method of treating autoimmunedisease. Exemplary autoimmune diseases include lupus erythematosus;Wiskott-Aldrich syndrome; autoimmune lymphoproliferative syndrome;myasthenia gravis; rheumatoid arthritis (RA); lupus nephritis; multiplesclerosis; systemic lupus erythematosis; discoid lupus; subacutecutaneous lupus erythematosus; cutaneous lupus erythematosus includingchilblain lupus erythematosus; chronic arthritis; Sjogren's syndrome;inflammatory chronic rhinosinusitis; colitis; celiac disease;inflammatory bowel disease; Barrett's esophagus; inflammatory gastritis;autoimmune nephritis; autoimmune vasculitis; autoimmune hepatitis;autoimmune carditis; autoimmune encephalitis; autoimmune diabetes;autoimmune diabetes nephritis; psoriasis; Graft-versus-host disease(GvHD); and autoimmune mediated hematological disease.

In one aspect of this embodiment, the method is a method of treatingimmune deficiency selected from the group consisting of AutoimmuneLymphoproliferative Syndrome (ALPS), Autoimmune polyglandular syndrometype 1 (APS-1), BENTA Disease, Caspase Eight Deficiency State (CEDS),Chronic Granulomatous Disease (CGD), Common Variable Immunodeficiency(CVID), Congenital Neutropenia Syndromes, CTLA4 Deficiency, DOCK8Deficiency, GATA2 Deficiency, Glycosylation Disorders WithImmunodeficiency, hyper-immunoglobulin E syndrome (HIES),Hyper-Immunoglobulin M (Hyper-IgM) Syndromes, Leukocyte adhesiondeficiency (LAD), LRBA deficiency, PI3 Kinase disease, PLCG2-associatedantibody deficiency and immune dysregulation (PLAID), severe combinedimmunodeficiency (SCID), STAT3 gain-of-function disease, Warts,Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome (WHIMS),X-Linked Agammaglobulinemia (XLA), X-Linked Lymphoproliferative Disease(XLP), and XMEN Disease.

As used herein, the term “immune deficiency” refers to a condition inwhich a portion or some portions of cell components constituting animmune system are defective or dysfunction, so that a normal immunemechanism is damaged. In other words, “immune deficiency” means acondition under which: congenital immunity and/or acquired immunity aresuppressed and/or decreased. In some embodiments, the immune-deficiencysubject is an immunocompromised subject. Non-limiting examples of immunedeficiencies can include AIDS, hypogammaglobulinemia,agammaglobulinemia, granulocyte deficiency, chronic granulomatousdisease, asplenia, SCID, complement deficiency, and/or sickle cellanemia.

In another aspect of this embodiment, the method is a method of treatinga neurodegenerative disorder selected from the group consisting ofmultiple sclerosis, Parkinson's disease (PD), Alzheimer's disease (AD),Dentatorubropallidoluysian atrophy (DRPLA), Huntington's Disease (HD),Spinocerebellar ataxia Type 1 (SCA1), Spinocerebellar ataxia Type 2(SCA2), Spinocerebellar ataxia Type 3 (SCA3), Spinocerebellar ataxia 6(SCA6), Spinocerebellar ataxia Type 7 (SCAT), Spinocerebellar ataxiaType 8 (SCAB), Spinocerebellar ataxia Type 12 (SCA12), Spinocerebellarataxia Type 17 (SCA17), Spinobulbar Muscular Ataxia/Kennedy Disease(SBMA), Fargile X syndrome (FRAXA), Fragile XE mental retardation(FRAXE), and Myotonic dystrophy (DM).

A “subject” is a mammal, preferably a human, but can also be an animalin need of veterinary treatment, e.g., companion animals (e.g., dogs,cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, andthe like) and laboratory animals (e.g., rats, mice, guinea pigs, and thelike).

In some embodiments, the methods disclosed herein further compriseco-administering an effective amount of a DNA repair inhibitor, a DNAdamage response (DDR) inhibitor, a DNA damaging agent or animmunomodulatory agent to the subject being treated for cancer, inaddition to an effective amount of a disclosed RAD51 inhibitor.

The term “DNA repair inhibitor” refers to any agent that targetscomponents/processes which a cell uses to repair mutations or changes inDNA and restore the DNA to its original state and prevents the repair ofDNA. Examples of DNA repair inhibitors include: RPA inhibitors, APE1inhibitors, DNA ligase inhibitors, DNA polymerase inhibitors, Parpinhibitors etc.

The term “DNA damage response inhibitor” refers to any agent thattargets components/processes involved in detecting DNA lesions,signaling the presence of DNA damage, and/or promote the repair of DNAdamage. Examples of DNA damage response inhibitors include checkpointinhibitors, ATM and ATR inhibitiors, DNA-PK inhibitors, etc.

The term “DNA damaging agent” refers to any agent that directly orindirectly damages DNA. The DNA damaging agents is selected from thegroup consisting of: exposure to a DNA damaging chemical; exposure to achemotherapeutic agent; exposure to a radiochemotherapy, and exposure toionizing or ultraviolet radiation. Specific examples of DNA-damagingchemotherapeutic agents include alkylating agents, nitrosoureas,anti-metabolites, plant alkaloids, plant extracts and radioisotopes.Specific examples of the chemotherapeutic agents also includeDNA-damaging drugs, for example, 5-fluorouracil (5-FU), capecitabine,S-1 (Tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid),5-ethynyluracil, arabinosyl cytosine (ara-C), 5-azacytidine (5-AC),2′,2′-difluoro-2′-deoxycytidine (dFdC), purine antimetabolites(mercaptopurine, azathiopurine, thioguanine), gemcitabine hydrochlorine(Gemzar), pentostatin, allopurinol, 2-fluoro-arabinosyl-adenine(2F-ara-A), hydroxyurea, sulfur mustard (bischloroetyhylsulfide),mechlorethamine, melphalan, chlorambucil, cyclophosphamide, ifosfamide,thiotepa, AZQ, mitomycin C, dianhydrogalactitol, dibromoducitol, alkylsulfonate (busulfan), nitrosoureas (BCNU, CCNU, 4-methyl CCNU or ACNU),procarbazine, decarbazine, rebeccamycin, anthracycline such asdoxorubicin (adriamycin; ADR), daunorubicin (Cerubicine), idarubicin(Idamycin) and epirubicin (Ellence), anthracyclin analogs such asmitoxantrone, actinimycin D, non-intercalating topoisomerase inhibitorssuch as epipodophyllotoxins (etoposide or VP16, teniposide or VM-26),podophylotoxin, bleomycin (Bleo), pepleomycin, compounds that formadducts with nucleic acid including platinum derivatives, e.g.,cisplatin (CDDP), trans analog of cisplatin, carboplatin, iproplatin,tetraplatin and oxaliplatin, as well as camptothecin, topotecan,irinotecan (CPT-11), and SN-38. Specific examples of nucleic aciddamaging treatments include radiation e.g., ultraviolet (UV), infrared(IR), or .alpha.-, .beta.-, or .gamma-radiation, as well asenvironmental shock, e.g., hyperthermia.

“Immunomodulatory agent” means an agent that modulates an immuneresponse to an antigen but is not the antigen or derived from theantigen. “Modulate”, as used herein, refers to inducing, enhancing,suppressing, directing, or redirecting an immune response. Such agentsinclude immunostimulatory agents, such as adjuvants, that stimulate (orboost) an immune response to an antigen but is not an antigen or derivedfrom an antigen. There are several distinct types of immunomodulatoryagents, which include, but are not limited to, Toll-like Receptor (TLR)agonists and Toll-like Receptor (TLR) antagonists. Such agents alsoinclude immunosuppressants. The immunomodulatory agent is selected fromthe group consisting of immune checkpoint modulators, Toll-like receptor(TLR) agonists, cell-based therapies, cytokines and cancer vaccines.

In some embodiments, the subject is determined to have an increasedlevel and/or activity of a DNA damage process or DNA editing enzyme. Inone aspect of this embodiment, the DNA editing enzyme is selected fromthe group consisting of activation induced cytidine deaminase (AID orAICDA), APOBEC2, APOBEC3A, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G,APOBEC3H, APOBEC4, a Type 1 Topoisomerase, a Type 2 Topoisomerase,Recombination Activating Gene 1 (RAG 1), and Recombination ActivatingGene 2 (RAG2).

In some embodiments, blood cells obtained from the subject have beendetermined to have a detectable level of activation-induced cytidinedeaminase (AID).

In some embodiments, B cells obtained from the subject have beendetermined to have a detectable level of activation-induced cytidinedeaminase (AID).

In some embodiments, the detectable level of activation-induced cytidinedeaminase (AID) is statistically significantly higher than the level ofAID expressed in unactivated B-cells or normal non-immune cells from ahealthy subject.

The precise amount of compound administered to provide an “effectiveamount” to the subject will depend on the mode of administration, thetype, and severity of the disease, and on the characteristics of thesubject, such as general health, age, sex, body weight, and tolerance todrugs. The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors. When administered in combinationwith other therapeutic agents, e.g., when administered in combinationwith an anti-cancer agent, an “effective amount” of any additionaltherapeutic agent(s) will depend on the type of drug used. Suitabledosages are known for approved therapeutic agents and can be adjusted bythe skilled artisan according to the condition of the subject, the typeof condition(s) being treated and the amount of a compound of theapplication being used by following, for example, dosages reported inthe literature and recommended in the Physician's Desk Reference (57thed., 2003).

The term “effective amount” means an amount when administered to thesubject which results in beneficial or desired results, includingclinical results, e.g., inhibits, suppresses or reduces the symptoms ofthe condition being treated in the subject as compared to a control. Forexample, a therapeutically effective amount can be given in unit dosageform (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg toabout 5 grams per day).

The terms “administer”, “administering”, “administration”, and the like,as used herein, refer to methods that may be used to enable delivery ofcompositions to the desired site of biological action. These methodsinclude, but are not limited to, intraarticular (in the joints),intravenous, intramuscular, intratumoral, intradermal, intraperitoneal,subcutaneous, orally, topically, intrathecally, inhalationally,transdermally, rectally, and the like. Administration techniques thatcan be employed with the agents and methods described herein are foundin e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics,current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (currentedition), Mack Publishing Co., Easton, Pa.

In addition, the disclosed RAD51 inhibitors can be co-administered withother therapeutic agents. As used herein, the terms “co-administration”,“administered in combination with”, and their grammatical equivalents,are meant to encompass administration of two or more therapeutic agentsto a single subject, and are intended to include treatment regimens inwhich the agents are administered by the same or different route ofadministration or at the same or different times. In some embodimentsthe one or more compounds described herein will be co-administered withother agents. These terms encompass administration of two or more agentsto the subject so that both agents and/or their metabolites are presentin the subject at the same time. They include simultaneousadministration in separate compositions, administration at differenttimes in separate compositions, and/or administration in a compositionin which both agents are present. Thus, in some embodiments, thecompounds described herein and the other agent(s) are administered in asingle composition. In some embodiments, the compounds described hereinand the other agent(s) are admixed in the composition.

The particular mode of administration and the dosage regimen will beselected by the attending clinician, taking into account the particularsof the case (e.g., the subject, the disease, the disease state involved,the particular treatment). Treatment can involve daily or multi-daily orless than daily (such as weekly or monthly etc.) doses over a period ofa few days to months, or even years. However, a person of ordinary skillin the art would immediately recognize appropriate and/or equivalentdoses looking at dosages of approved compositions for treating a RAD51mediated disease using the disclosed RAD51 inhibitors for guidance.

The compounds or the corresponding pharmaceutical compositions taughtherein can be administered to a patient in a variety of forms dependingon the selected route of administration, as will be understood by thoseskilled in the art. The compounds of the present teachings may beadministered, for example, by oral, parenteral, buccal, sublingual,nasal, rectal, patch, pump or transdermal administration and thepharmaceutical compositions formulated accordingly. Parenteraladministration includes intravenous, intraperitoneal, subcutaneous,intramuscular, transepithelial, nasal, intrapulmonary, intrathecal,rectal and topical modes of administration. Parenteral administrationcan be by continuous infusion over a selected period of time.

The pharmaceutical composition of the application is formulated to becompatible with its intended route of administration. In an embodiment,the composition is formulated in accordance with routine procedures as apharmaceutical composition adapted for intravenous, subcutaneous,intramuscular, oral, intranasal, or topical administration to humanbeings. In preferred embodiments, the pharmaceutical composition isformulated for intravenous administration.

Typically, for oral therapeutic administration, a compound of thepresent teachings may be incorporated with excipient and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like.

Typically for parenteral administration, solutions of a compound of thepresent teachings can generally be prepared in water suitably mixed witha surfactant such as hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, DMSO and mixturesthereof with or without alcohol, and in oils. Under ordinary conditionsof storage and use, these preparations contain a preservative to preventthe growth of microorganisms.

Typically, for injectable use, sterile aqueous solutions or dispersionof, and sterile powders of, a compound described herein for theextemporaneous preparation of sterile injectable solutions ordispersions are appropriate.

EXAMPLES

Abbreviations Ac acetyl ACN acetonitrile aq aqueous Bn benzyl Boctert-butoxycarbonyl br. Broad CAN cerium ammonium nitrate d doublet(when in reference to an ¹H NMR spectra) DCM dichloromethane DIEAdiisopropylethylamine (DIPEA) DMA dimethylacetamide DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxidedppf 1,1′-bis(diphenylphosphino) ferrocene eq equivalent EtOAc ethylacetate h hour HBTUN,N,N′,N′,-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate HPLC high performance liquid chromatography LC-MSliquid chromatography coupled to mass spectrometry m multiplet (when inreference to an ¹H NMR spectra) MS ESI mass spectra, electrosprayionization NBS N-bromosuccinimide NMR nuclear magnetic resonance preppreparative Py pyridine s singlet (when in reference to an ¹H NMRspectra) sat saturated SFC supercritical fluid chromatography t triplet(when in reference to an ¹H NMR spectra) TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatographyTol toluene

Example 1 Preparation of isopropyl(trans-4-(5-(4-(aminomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 1)

a) Synthesis of 4-bromo-3-(tert-butylsulfamoyl)benzamide (General MethodA)

To a solution of 4-bromo-3-(tert-butylsulfamoyl)benzoic acid (1.9 g,5.65 mmol, 1.0 eq.) and DIEA (84.77 mmol, 14.77 mL, 15.0 eq.) in DMF (50mL) was added NH₄Cl (3.02 g, 56.51 mmol, 10.0 eq.) and HATU (2.79 g,7.35 mmol, 1.3 eq.). The mixture was stirred at 25° C. for 12 h, thenpoured into H₂O (200 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated to give4-bromo-3-(tert-butylsulfamoyl)benzamide (2.2 g, crude) as a yellow gum.[M+H]=335.0/337.0.

b) Synthesis of 5-(aminomethyl)-2-bromo-N-tert-butyl-benzene sulfonamide

To a solution of 4-bromo-3-(tert-butylsulfamoyl)benzamide (1 g, 2.98mmol, 1.0 eq.) in THF (30 mL) was added BH₃-Me₂S (10 M in THF, 1.49 mL,5 eq.). The mixture was stirred at 50° C. for 2 h. The reaction mixturewas quenched by 1N HCl (2 mL) at 0° C., stirred at 50° C. for 1 hr, thenconcentrated under reduced pressure to give5-(aminomethyl)-2-bromo-N-tert-butyl-benzenesulfonamide (1.5 g, crude,HCl salt) as a white solid. [M+H]=321.1/323.1.

c) Synthesis of tert-butylN-[[4-bromo-3-(tert-butylsulfamoyl)phenyl]methyl]carbamate

To a solution of 5-(aminomethyl)-2-bromo-N-tert-butyl-benzenesulfonamide(HCl salt, 1.5 g, 4.67 mmol, 1.0 eq.) and Boc₂O (1.22 g, 5.60 mmol, 1.2eq.) in MeOH (10 mL) and H₂O (10 mL) was added Na₂CO₃ (990 mg, 9.34mmol, 2.0 eq.). The mixture was stirred at 25° C. for 12 h under N₂atmosphere and then concentrated. The residue was purified by prep-HPLCto give tert-butylN-[[4-bromo-3-(tert-butylsulfamoyl)phenyl]methyl]carbamate (190 mg, 451umol, 10% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=7.99 (d,J=1.3 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.27-7.22 (m, 1H), 4.25 (br d,J=5.7 Hz, 2H), 1.38 (s, 9H), 1.14 (s, 9H). [M+Na]=443.1/445.1.

d) Synthesis of tert-butylN-[[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate(General Method B)

A mixture of tert-butylN-[[4-bromo-3-(tert-butylsulfamoyl)phenyl]methyl]carbamate (180 mg,427.2 umol, 1.0 eq.), B₂Pin₂ (326 mg, 1.28 mmol, 3.0 eq.), KOAc (126 mg,1.28 mmol, 3.0 eq.) and Pd(dppf)Cl₂.CH₂Cl₂ (35 mg, 42.7 umol, 0.1 eq.)in dioxane (5 mL) was degassed and purged with N₂ for 3 times andstirred at 80° C. for 12 h. The reaction mixture was concentrated andthe residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethylacetate=3/1) to give tert-butylN-[[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate(20 mg, 42.7 umol, 10% yield) as a yellow gum. ESI [M+H]=469.2.

e) Synthesis of isopropylN-[trans-4-[5-[4-[(tert-butoxycarbonylamino)methyl]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(General Method C)

A mixture of tert-butylN-[[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate(20 mg, 42.7 umol, 1.0 eq.), isopropyl(trans-4-(5-bromothiazol-2-yl)cyclohexyl)carbamate (18 mg, 51.2 umol,1.2 eq.), Na₂CO₃ (14 mg, 128 umol, 3.0 eq.), Pd(PPh₃)₄ (4.9 mg, 4.3umol, 0.1 eq.) and KF (7.4 mg, 128 umol, 3.0 uL, 3.0 eq.) in EtOH (1mL)/H₂O (0.3 mL)/Tol. (1 mL) was degassed and purged with N₂ for 3 timesand then stirred at 80° C. for 12 h. The reaction mixture wasconcentrated and the residue was purified by prep-TLC (SiO₂, Petroleumether/Ethyl acetate=2/1) to give isopropylN-[trans-4-[5-[4-[(tert-butoxycarbonylamino)methyl]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(20 mg, crude) as a yellow gum. ESI [M+H]=609.3.

f) Synthesis of isopropyl(trans-4-(5-(4-(aminomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 1)

A solution of isopropylN-[trans-4-[5-[4-[(tert-butoxycarbonylamino)methyl]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(20 mg, crude) in HCl/MeOH (4 M, 1 mL) was stirred at 25° C. for 30mins. The reaction mixture was concentrated and the residue was purifiedby prep-HPLC (column: Nano-Micro UniSil 5-100 C18 ULTRA 100*250 mm 5 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 30%-60%,10 min) to giveisopropyl(trans-4-(5-(4-(aminomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(1.03 mg, 1.47 umol, 89% purity, TFA salt) as a pale yellow solid. ¹HNMR (400 MHz, methanol-d₄) δ=8.32 (d, J=1.7 Hz, 1H), 7.81 (s, 1H),7.75-7.70 (m, 1H), 7.60 (d, J=7.8 Hz, 1H), 4.86-4.82 (m, 1H), 4.28 (s,2H), 3.52-3.43 (m, 1H), 3.11-3.00 (m, 1H), 2.26 (br d, J=13.7 Hz, 2H),2.09 (br d, J=11.1 Hz, 2H), 1.79-1.68 (m, 2H), 1.50-1.37 (m, 2H), 1.25(br d, J=6.1 Hz, 6H), 1.09 (s, 9H). ESI [M+H]=509.2.

Example 2 Preparation of isopropyl(trans-4-(5-(4-(acetamidomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 2)

a) Synthesis ofN-[[4-bromo-3-(tert-butylsulfamoyl)phenyl]methyl]acetamide

To a solution of 5-(aminomethyl)-2-bromo-N-tert-butyl-benzenesulfonamide(0.4 g, 1.25 mmol, 1.0 eq.) in DCM (5 mL) were added DIEA (6.25 mmol,1.1 mL, 5.0 eq.), DMAP (15.2 mg, 125 umol, 0.1 eq.) and Ac₂O (153 mg,1.5 mmol, 1.2 eq.). The mixture was stirred at 25° C. for 1 hr, thenpoured into H₂O (20 mL) and extracted with EtOAc (20 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to giveN-[[4-bromo-3-(tert-butylsulfamoyl)phenyl]methyl]acetamide (320 mg,crude) as a yellow oil. ESI [M+H]=363.1/365.1

b) Synthesis ofN-[[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]acetamide

A mixture of N-[[4-bromo-3-(tert-butylsulfamoyl)phenyl]methyl]acetamide(0.3 g, 826 umol, 1.0 eq.), B₂Pin₂ (629 mg, 2.5 mmol, 3.0 eq.), KOAc(243 mg, 2.5 mmol, 3 eq.) and Pd(dppf)Cl₂.CH₂Cl₂ (67.5 mg, 82.6 umol,0.1 eq.) in dioxane (5 mL) was degassed and purged with N₂ for 3 timesand then stirred at 80° C. for 12 h. The reaction mixture wasconcentrated and the residue was purified by column chromatography(SiO₂, Petroleum ether/Ethyl acetate=10/1 to 0:1) to giveN-[[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]acetamide(70 mg, 171 umol, 21% yield) as a yellow gum. ESI [M+H]=411.3.

c) Synthesis of isopropyl(trans-4-(5-(4-(acetamidomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 2)

A mixture ofN-[[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]acetamide(66 mg, 161 umol, 0.93 eq.), isopropylN-[trans-4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (60 mg, 173 umol,1.0 eq.), Na₂CO₃ (54.9 mg, 518 umol, 3.0 eq.), KF (30.1 mg, 518 umol,3.0 eq.) and Pd(PPh₃)₄ (19.9 mg, 17.3 umol, 0.1 eq.) in H₂O (0.3mL)/EtOH (1.0 mL)/Tol. (1.0 mL) was degassed and purged with N₂ for 3times. The mixture was stirred at 80° C. for 12 h under N₂ atmosphereand then concentrated. The residue was purified by prep-TLC (SiO₂,Petroleum ether/Ethyl acetate=1/1) to give isopropyl(trans-4-(5-(4-(acetamidomethyl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(16.99 mg, 30.85 umol, 18% yield, 100% purity) as a white solid. ¹H NMR(400 MHz, methanol-d₄) δ=8.10 (d, J=1.6 Hz, 1H), 7.81 (s, 1H), 7.57 (dd,J=1.6, 7.9 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 4.88-4.81 (m, 1H), 4.48 (s,2H), 3.52-3.43 (m, 1H), 3.07 (br t, J=12.2 Hz, 1H), 2.26 (br d, J=12.1Hz, 2H), 2.10 (br d, J=9.9 Hz, 2H), 2.04 (s, 3H), 1.80-1.66 (m, 2H),1.50-1.38 (m, 2H), 1.24 (d, J=6.1 Hz, 6H), 1.11 (s, 9H). ESI[M+H]=551.2.

Example 3 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 3)

a) Synthesis of isopropyl(trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate

To a solution of tert-butyl nitrite (2.2 g, 21.2 mmol, 1.5 eq.) in MeCN(20 mL) was added CuBr₂ (3.16 g, 14.2 mmol, 1.0 eq.) and isopropyl(trans-4-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(7.0 g, 14.2 mmol, 1.0 eq.). The mixture was stirred at 60° C. for 1 hr,then poured into 1N NaHCO₃ solution (100 mL) at 25° C. and extractedwith EtOAc (50 mL×3). The combined organic layers dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=10:1 to 5:1 to 0:1)to give isopropyl(trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (4.2 g, 7.52 mmol, 53% yield) as a white solid. ¹HNMR (400 MHz, methanol-d₄) δ=8.29 (d, J=2.1 Hz, 1H), 7.79 (s, 2H), 7.42(d, J=8.2 Hz, 1H), 4.84 (br d, J=6.4 Hz, 1H), 3.53-3.43 (m, 1H), 3.03(s, 1H), 2.25 (br d, J=12.5 Hz, 2H), 2.13-2.06 (m, 2H), 1.77-1.64 (m,2H), 1.43 (br dd, J=2.4, 12.6 Hz, 2H), 1.25 (dd, J=2.0, 6.7 Hz, 6H),1.13-1.08 (m, 9H). ESI [M+H]=558.1/560.1.

b) Synthesis of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 3; General Method D)

A mixture of isopropyl(trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (40 mg, 71.6 umol, 1.0 eq.),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine(21 mg, 86 umol, 1.2 eq.), KOAc (21.08 mg, 214.84 umol, 3.0 eq.) andPd(AmPhos)Cl₂ (5.07 mg, 7.16 umol, 0.1 eq.) in EtOH (1 mL)/H₂O (0.25 mL)was degassed and purged with N₂ for 3 times, and then stirred at 80° C.for 12 h. The reaction mixture was concentrated and the residue waspurified by prep-HPLC (column: Welch Ultimate AQ-C18 150*30 mm*5 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 50%-80%,12 min) to giveisopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(22.64 mg, 37.62 umol, 52.53% yield, 99% purity) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ=8.82 (d, J=7.0 Hz, 1H), 8.52 (s, 1H), 8.34 (d,J=1.8 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.98-7.94 (m, 1H), 7.77 (s, 1H),7.56 (d, J=7.9 Hz, 1H), 7.50-7.43 (m, 1H), 7.17 (s, 1H), 7.09-7.00 (m,2H), 4.76 (td, J=6.2, 12.5 Hz, 1H), 2.95 (tt, J=3.6, 11.9 Hz, 1H), 2.16(br d, J=11.6 Hz, 2H), 1.94 (br d, J=10.4 Hz, 2H), 1.68-1.55 (m, 2H),1.43-1.31 (m, 2H), 1.18 (d, J=6.2 Hz, 6H), 1.08 (s, 9H). ESI[M+H]=596.2.

Example 4 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 4)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.43 (s, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.12 (s,1H), 7.84 (dd, J=1.8, 7.9 Hz, 1H), 7.70 (s, 1H), 7.45 (d, J=7.9 Hz, 1H),7.07-6.89 (m, 2H), 5.17 (q, J=9.0 Hz, 2H), 4.71 (td, J=6.2, 12.3 Hz,1H), 3.36-3.21 (m, 1H), 2.89 (ddd, J=3.3, 8.5, 11.7 Hz, 1H), 2.11 (br d,J=11.7 Hz, 2H), 1.89 (br d, J=10.4 Hz, 2H), 1.55 (dq, J=2.5, 12.7 Hz,2H), 1.37-1.25 (m, 2H), 1.13 (d, J=6.2 Hz, 6H), 1.01 (s, 9H). ESI[M+H]=628.2.

Example 5 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(pyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 5)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=9.21 (s, 1H), 8.84 (br d, J=5.1 Hz, 1H), 8.67(br d, J=7.9 Hz, 1H), 8.41 (s, 1H), 8.07 (br d, J=7.9 Hz, 1H), 8.00-7.89(m, 1H), 7.77 (s, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.10 (s, 1H), 6.98 (br d,J=7.1 Hz, 1H), 4.71 (td, J=6.0, 12.2 Hz, 1H), 3.37-3.23 (m, 1H), 2.92(br t, J=11.8 Hz, 1H), 2.12 (br d, J=12.1 Hz, 2H), 1.90 (br d, J=11.0Hz, 2H), 1.63-1.49 (m, 2H), 1.38-1.27 (m, 2H), 1.13 (d, J=6.2 Hz, 6H),1.00 (s, 9H). ESI [M+H]=557.2.

Example 6 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(1H-pyrazol-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 6)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.52 (d, J=1.54 Hz, 1H), 7.99 (dd, J=1.76, 7.94Hz, 1H), 7.81 (d, J=1.98 Hz, 1H), 7.73 (s, 1H), 7.49 (d, J=7.94 Hz, 1H),7.07 (s, 1H), 7.00 (br d, J=7.50 Hz, 1H), 6.81 (d, J=2.21 Hz, 1H), 4.73(td, J=6.17, 12.35 Hz, 1H), 3.31 (br d, J=7.94 Hz, 1H), 2.85-2.98 (m,1H), 2.13 (br d, J=12.35 Hz, 2H), 1.91 (br d, J=9.92 Hz, 2H), 1.50-1.67(m, 2H), 1.25-1.43 (m, 2H), 1.15 (d, J=6.39 Hz, 6H), 1.04 (s, 9H). ESI[M+H]=546.2.

Example 7 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(6-hydroxypyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 7)

From isopropyl(trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate,using the corresponding boric acid or boronate and under the samereaction conditions as for Compound 3. ¹H NMR (400 MHz, DMSO-d₆) δ=8.17(d, J=1.8 Hz, 1H), 7.93-7.81 (m, 3H), 7.74 (br s, 1H), 7.50 (d, J=8.1Hz, 1H), 7.11 (br s, 1H), 7.03 (br d, J=7.6 Hz, 1H), 6.50 (d, J=9.4 Hz,1H), 4.75 (td, J=6.1, 12.4 Hz, 1H), 3.40-3.24 (m, 1H), 2.95 (br d, J=9.9Hz, 1H), 2.15 (br d, J=12.2 Hz, 2H), 1.93 (br d, J=10.0 Hz, 2H),1.68-1.52 (m, 2H), 1.41-1.30 (m, 2H), 1.17 (d, J=6.2 Hz, 6H), 1.05 (s,9H). ESI [M+H]=573.2.

Example 8 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2,4-dimethoxypyrimidin-5-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 8)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.50 (s, 1H), 8.25 (d, J=1.8 Hz, 1H), 7.86-7.72(m, 2H), 7.56 (d, J=8.1 Hz, 1H), 7.21 (s, 1H), 7.05 (br d, J=7.8 Hz,1H), 4.75 (td, J=6.1, 12.4 Hz, 1H), 3.98 (d, J=4.0 Hz, 6H), 3.42-3.26(m, 1H), 2.94 (tt, J=3.5, 11.9 Hz, 1H), 2.16 (br d, J=12.0 Hz, 2H), 1.93(br d, J=10.0 Hz, 2H), 1.67-1.52 (m, 2H), 1.44-1.27 (m, 2H), 1.17 (d,J=6.2 Hz, 6H), 1.13-1.03 (m, 9H). ESI [M+H]=618.3.

Example 9 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2H-indazol-6-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 9)

From isopropyl(trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate,using the corresponding boric acid or boronate and under the samereaction conditions as for Compound 3. ¹H NMR (400 MHz, DMSO-d₆) δ=8.39(d, J=1.7 Hz, 1H), 8.15 (s, 1H), 8.02 (dd, J=1.8, 8.0 Hz, 1H), 7.93 (d,J=8.3 Hz, 1H), 7.84 (s, 1H), 7.79 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.49(d, J=8.4 Hz, 1H), 7.21 (s, 1H), 7.03 (br d, J=7.6 Hz, 1H), 4.76 (td,J=6.2, 12.4 Hz, 1H), 3.34 (br d, J=7.3 Hz, 1H), 3.01-2.90 (m, 1H), 2.17(br d, J=12.1 Hz, 2H), 1.94 (br d, J=10.4 Hz, 2H), 1.67-1.53 (m, 2H),1.43-1.30 (m, 2H), 1.18 (d, J=6.2 Hz, 6H), 1.09 (s, 9H). ESI[M+H]=596.3.

Example 10 Preparation of isopropyl(trans-4-(5-(4-(2-aminopyrimidin-5-yl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 10)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.66 (s, 2H), 8.23 (d, J=1.7 Hz, 1H), 7.90 (dd,J=1.8, 8.0 Hz, 1H), 7.78-7.69 (m, 1H), 7.53 (d, J=7.9 Hz, 1H), 7.10 (s,1H), 7.05-6.97 (m, 3H), 4.75 (td, J=6.2, 12.4 Hz, 1H), 3.42-3.26 (br s,1H),2.94 (tt, J=3.5, 11.8 Hz, 1H), 2.15 (br d, J=12.0 Hz, 2H), 1.93 (brd, J=10.3 Hz, 2H), 1.67-1.51 (m, 2H), 1.43-1.27 (m, 2H), 1.17 (d, J=6.2Hz, 6H), 1.06 (s, 9H). ESI [M+H]=573.2.

Example 11 Preparation of isopropyl(trans-4-(5-(4-(benzofuran-5-yl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 11)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.32 (d, J=2.0 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H),8.01 (d, J=1.5 Hz, 1H), 7.95 (dd, J=2.0, 7.9 Hz, 1H), 7.77-7.71 (m, 2H),7.68-7.64 (m, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.12 (s, 1H), 7.07-7.04 (m,1H), 7.03-6.98 (m, 1H), 4.78-4.68 (m, 1H), 3.27 (br s, 1H), 2.98-2.86(m, 1H), 2.21-2.09 (m, 2H), 1.91 (br dd, J=2.0, 12.3 Hz, 2H), 1.56 (brd, J=2.2 Hz, 2H), 1.40-1.27 (m, 2H), 1.15 (d, J=6.2 Hz, 6H), 1.05 (s,9H). ESI [M+H]=596.2.

Example 12 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(pyrimidin-5-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 12)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=9.23 (s, 1H), 9.18 (s, 2H), 8.37 (d, J=2.0 Hz,1H), 8.05 (dd, J=1.9, 8.0 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J=7.9 Hz, 1H),7.13 (s, 1H), 7.01 (br d, J=7.7 Hz, 1H), 4.71 (s, 1H), 3.31 (br d,J=7.72 Hz, 1H),2.97-2.86 (m, 1H), 2.12 (br d, J=11.7 Hz, 2H), 1.89 (brd, J=10.1 Hz, 2H), 1.56 (dq, J=2.9, 12.8 Hz, 2H), 1.36-1.25 (m, 2H),1.13 (d, J=6.4 Hz, 6H), 1.02 (s, 9H). ESI [M+H]=558.2.

Example 13 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3,6-dimethoxypyridazin-4-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 13)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ 8.33 (d, J=1.76 Hz, 1H), 7.87 (dd, J=1.76, 7.94Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=7.94 Hz, 1H), 7.35 (s, 1H), 7.22 (s,1H), 6.93-7.05 (m, 1H), 4.73 (td, J=6.17, 12.35 Hz, 1H), 3.99 (d, J=2.20Hz, 6H), 3.31 (br d, J=7.72 Hz, 1H), 2.81-3.01 (m, 1H), 2.13 (br d,J=12.57 Hz, 2H), 1.84-1.99 (m, 2H), 1.49-1.64 (m, 2H), 1.24-1.43 (m,2H), 1.15 (d, J=6.17 Hz, 6H), 1.08 (s, 9H). ESI [M+H]=618.2.

Example 14 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-methylthiazol-5-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 14)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.24-8.15 (m, 2H), 7.93 (dd, J=2.0, 8.1 Hz,1H), 7.77 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.27 (s, 1H), 7.03 (br d,J=7.7 Hz, 1H), 4.75 (td, J=6.2, 12.4 Hz, 1H), 3.39-3.25 (m, 1H), 2.94(tt, J=3.4, 11.8 Hz, 1H), 2.72 (s, 3H), 2.15 (br d, J=11.9 Hz, 2H), 1.93(br d, J=10.5 Hz, 2H), 1.59 (dq, J=2.9, 12.7 Hz, 2H), 1.41-1.29 (m, 2H),1.17 (d, J=6.2 Hz, 6H), 1.07 (s, 9H). ESI [M+H]=577.2.

Example 15 Preparation of isopropyl(trans-4-(5-(4-(benzo[d]thiazol-6-yl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 15)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=9.47 (s, 1H), 8.63 (d, J=1.6 Hz, 1H), 8.42 (d,J=2.0 Hz, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.05 (dd, J=2.0, 8.1 Hz, 1H),7.92 (dd, J=1.8, 8.6 Hz, 1H), 7.79 (s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.14(s, 1H), 7.09-6.95 (m, 1H), 4.76 (td, J=6.3, 12.4 Hz, 1H), 3.34 (br d,J=4.6 Hz, 1H), 3.02-2.89 (m, 1H), 2.17 (br d, J=11.9 Hz, 2H), 1.94 (brd, J=10.4 Hz, 2H), 1.68-1.54 (m, 2H), 1.42-1.30 (m, 2H), 1.18 (d, J=6.2Hz, 6H), 1.07 (s, 9H). ESI [M+H]=613.2.

Example 16 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(5-((dimethylamino)methyl)pyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 16)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=9.08 (d, J=2.1 Hz, 1H), 8.75 (d, J=1.7 Hz, 1H),8.42 (d, J=1.8 Hz, 1H), 8.36 (s, 1H), 8.07 (dd, J=2.0, 7.9 Hz, 1H), 7.80(s, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.14-6.96 (m, 2H), 4.75 (td, J=6.1,12.4 Hz, 1H), 4.46 (br s, 2H), 3.45-3.25 (m, 1H), 3.07-2.89 (m, 1H),2.83 (br s, 6H), 2.17 (br d, J=11.7 Hz, 2H), 1.94 (br d, J=10.3 Hz, 2H),1.69-1.52 (m, 2H), 1.46-1.27 (m, 2H), 1.17 (d, J=6.2 Hz, 6H), 1.03 (s,9H). ESI [M+H]=614.3.

Example 17 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(5-methyl-1H-pyrazol-4-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 17)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.12 (d, J=1.8 Hz, 1H), 7.93 (s, 1H), 7.76-7.69(m, 2H), 7.48 (d, J=7.9 Hz, 1H), 7.15-7.00 (m, 2H), 4.75 (td, J=6.2,12.5 Hz, 1H), 3.40-3.26 (m, 1H), 2.93 (tt, J=3.4, 11.8 Hz, 1H), 2.43 (s,3H), 2.15 (br d, J=12.0 Hz, 2H), 1.93 (br d, J=10.4 Hz, 2H), 1.59 (dq,J=2.8, 12.7 Hz, 2H), 1.41-1.29 (m, 2H), 1.17 (d, J=6.2 Hz, 6H), 1.07 (s,9H). ESI [M+H]=560.2.

Example 18 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(6-cyanopyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 18)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, methanol-d₄) δ=9.08 (d, J=1.5 Hz, 1H), 8.49 (d, J=2.2 Hz,1H), 8.36-8.32 (m, 1H), 8.04-7.99 (m, 2H), 7.85-7.83 (m, 1H), 7.67 (d,J=7.9 Hz, 1H), 4.81-4.75 (m, 1H), 3.48-3.44 (m, 1H), 3.07-3.03 (m, 1H),2.27-2.23 (m, 2H), 2.10-2.05 (m, 2H), 1.75-1.69 (m, 2H), 1.46-1.40 (m,2H), 1.25-1.19 (m, 6H), 1.10 (s, 9H). ESI [M+H]=582.2.

Example 19 Preparation of isopropyl(trans-4-(5-(4-(1H-benzo[d][1,2,3]triazol-6-yl)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 19)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.38 (d, J=2.0 Hz, 1H), 8.23 (br s, 1H),8.08-8.01 (m, 2H), 7.82-7.74 (m, 2H), 7.59 (d, J=7.9 Hz, 1H), 7.18 (s,1H), 7.00 (br d, J=7.5 Hz, 1H), 4.73 (td, J=6.2, 12.3 Hz, 1H), 3.31 (td,J=3.7, 7.3 Hz, 1H), 2.96-2.89 (m, 1H), 2.14 (br d, J=11.9 Hz, 2H), 1.91(br d, J=9.9 Hz, 2H), 1.58 (dq, J=2.8, 12.8 Hz, 2H), 1.39-1.29 (m, 2H),1.15 (d, J=6.2 Hz, 6H), 1.06 (s, 9H). ESI [M+H]=597.2.

Example 20 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(6-(hydroxymethyl)pyridin-3-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 20)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.92 (s, 1H), 8.36 (d, J=1.6 Hz, 2H), 8.08-8.01(m, 1H), 7.79 (s, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H),7.19 (s, 1H), 7.04 (br d, J=8.2 Hz, 1H), 4.78-4.73 (m, 1H), 4.70 (s,2H), 3.39-3.29 (m, 1H), 3.01-2.89 (m, 1H), 2.16 (br d, J=12.7 Hz, 2H),1.97-1.90 (m, 2H), 1.60 (dd, J=2.6, 12.4 Hz, 2H), 1.42-1.31 (m, 2H),1.18 (d, J=6.2 Hz, 6H), 1.06 (s, 9H). ESI [M+H]=587.2.

Example 21 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(3-methyl-1H-indol-6-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 21)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.35 (d, J=2.0 Hz, 1H), 7.95 (dd, J=2.0, 8.1Hz, 1H), 7.77 (s, 1H), 7.68 (d, J=0.9 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H),7.55 (d, J=8.1 Hz, 1H), 7.38 (dd, J=1.5, 8.3 Hz, 1H), 7.22 (d, J=0.9 Hz,1H), 7.17 (s, 1H), 7.04 (br d, J=7.8 Hz, 1H), 4.76 (s, 1H), 3.39-3.28(m, 1H), 2.99-2.90 (m, 1H), 2.30 (d, J=0.6 Hz, 3H), 2.17 (br d, J=11.5Hz, 2H), 1.94 (br d, J=10.1 Hz, 2H), 1.60 (dq, J=2.8, 12.7 Hz, 2H),1.42-1.28 (m, 2H), 1.18 (d, J=6.2 Hz, 6H), 1.09 (s, 9H). ESI[M+H]=609.3.

Example 22 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-(trifluoromethyl)pyridin-4-yl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 22)

From isopropyl (trans-4-(5-(4-bromo-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate, using the corresponding boric acid orboronate and under the same reaction conditions as for Compound 3. ¹HNMR (400 MHz, DMSO-d₆) δ=8.91 (d, J=5.0 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H),8.27 (s, 1H), 8.21 (dd, J=1.8, 8.1 Hz, 1H), 8.13 (d, J=4.9 Hz, 1H), 7.81(s, 1H), 7.69 (d, J=8.1 Hz, 1H), 7.24 (s, 1H), 7.03 (br d, J=7.8 Hz,1H), 4.80-4.71 (m, 1H), 3.40-3.27 (m, 1H), 2.90 (s, 1H), 2.17 (br d,J=11.7 Hz, 2H), 1.98-1.88 (m, 2H), 1.67-1.54 (m, 2H), 1.41-1.29 (m, 2H),1.17 (d, J=6.2 Hz, 6H), 1.06 (s, 9H). ESI [M+H]=625.2.

Example 23 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 23) and isopropyl(trans-4-(5-(4-hydroxy-2-sulfamoylphenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 24)

Isopropyl(trans-4-(5-(4-amino-2-(N-(tert-butypsulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(1 g, 2.02 mmol, 1.0 eq.) was dissolved in H₂SO₄ (30%, aq., 12 mL),cooled to 0° C. and added a solution of NaNO₂ (279 mg, 4.04 mmol, 2.0eq.) in H₂O (2 mL). The mixture was stirred at 0° C. for 1 hr, thenadded H₂O (28 mL) and the mixture was stirred at 65° C. for 11 h. Thereaction mixture was concentrated and the residue was purified byprep-HPLC (column: Xtimate C18 10μ 250 mm*50 mm; mobile phase:[water(0.1% TFA)-ACN]; B %: 30%-60%,20 min) to give isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 23) (0.3 g, 581 umol, 28.74% yield, 96% purity) as a yellowsolid and isopropyl(trans-4-(5-(4-hydroxy-2-sulfamoylphenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 24) (0.3 g, 669 umol, 33% yield, 98% purity) as a yellowsolid.

¹H NMR (400 MHz, methanol-d₄) δ=7.75 (s, 1H), 7.60 (d, J=2.6 Hz, 1H),7.32 (d, J=8.4 Hz, 1H), 7.03 (dd, J=2.6, 8.4 Hz, 1H), 4.87-4.81 (m, 1H),3.47 (tt, J=3.8, 11.6 Hz, 1H), 3.06 (tt, J=3.5, 12.1 Hz, 1H), 2.30-2.21(m, 2H), 2.14-2.03 (m, 2H), 1.72 (dq, J=3.1, 12.8 Hz, 2H), 1.43 (dq,J=3.2, 12.6 Hz, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.13 (s, 9H). ESI[M+H]=496.2.

¹H NMR (400 MHz, methanol-d₄) δ=7.77 (s, 1H), 7.58 (d, J=2.6 Hz, 1H),7.33 (d, J=8.3 Hz, 1H), 7.03 (dd, J=2.6, 8.3 Hz, 1H), 4.87-4.82 (m, 1H),3.47 (tt, J=4.0, 11.6 Hz, 1H), 3.06 (tt, J=3.3, 12.0 Hz, 1H), 2.29-2.18(m, 2H), 2.15-2.00 (m, 2H), 1.72 (dq, J=2.9, 12.8 Hz, 2H), 1.43 (dq,J=3.4, 12.6 Hz, 2H), 1.24 (br d, J=6.1 Hz, 6H). ESI [M+H]=440.1.

Example 24 Preparation of isopropylN-[trans-4-[5-[4-[2-(tert-butoxycarbonylamino)ethoxy]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 25)

To a solution of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate(50 mg, 101 umol, 1.0 eq.) in DMF (1 mL) was added K₂CO₃ (42 mg, 303umol, 3.0 eq.) and tert-butyl N-(2-bromoethyl) carbamate (27 mg, 121umol, 1.2 eq.). The mixture was stirred at 50° C. for 12 h, then dilutedwith sat.aq.LiCl (10 mL) and extracted with EtOAc (20 mL×2). Thecombined organic layers were washed with sat.aq.LiCl (10 mL×2), driedover Na₂SO₄, filtered and concentrated. The residue was purified byprep-HPLC (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water(10mM NH₄HCO₃)-ACN]; B %: 50%-80%,8 min) to give isopropylN-[trans-4-[5-[4-[2-(tert-butoxycarbonylamino)ethoxy]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(4.98 mg, 7.72 umol, 8% yield, 99% purity) as a white solid. ¹H NMR (400MHz, methanol-d₄) δ=7.76-7.68 (m, 2H), 7.41 (d, J=8.6 Hz, 1H), 7.21 (dd,J=2.7, 8.6 Hz, 1H), 4.86-4.81 (m, 1H), 4.13 (t, J=5.4 Hz, 2H), 3.49 (t,J=5.4 Hz, 2H), 3.44 (br s, 1H), 3.09-2.95 (m, 1H), 2.25 (br d, J=12.5Hz, 2H), 2.09 (br d, J=10.9 Hz, 2H), 1.79-1.62 (m, 2H), 1.47 (s, 9H),1.45-1.36 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.12 (s, 9H). ESI[M+H]=639.3.

Example 25 Preparation of isopropyl(trans-4-(5-(4-(2-aminoethoxy)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 26)

A solution of isopropylN-[trans-4-[5-[4-[2-(tert-butoxycarbonylamino)ethoxy]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(75 mg, 117.4 umol) in HCl/MeOH (4 M, 1 mL) was stirred at 25° C. for0.5 hr. The mixture was then concentrated and purified by prep-HPLC(column: Nano-Micro UniSil 5-100 C18 ULTRA 100×250 mm 5 um; mobilephase: [water(0.1% TFA)-ACN]; B %: 25%-45%,10 min) to give isopropyl(trans-4-(5-(4-(2-aminoethoxy)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(10.21 mg, 15.64 umol, 13% yield, 100% purity, TFA salt) as a yellowsolid. ¹H NMR (400 MHz, methanol-d₄) δ=7.69 (d, J=2.7 Hz, 1H), 7.60 (s,1H), 7.35 (d, J=8.4 Hz, 1H), 7.17 (dd, J=2.7, 8.6 Hz, 1H), 4.74-4.68 (m,1H), 4.24 (t, J=5.0 Hz, 2H), 3.40-3.35 (m, 1H), 3.32 (br t, J=4.8 Hz,2H), 2.91 (tt, J=3.5, 12.0 Hz, 1H), 2.13 (br d, J=12.0 Hz, 2H), 1.97 (brd, J=9.9 Hz, 2H), 1.59 (dq, J=2.8, 12.8 Hz, 2H), 1.31 (dq, J=3.2, 12.6Hz, 2H), 1.13 (br d, J=6.1 Hz, 6H), 0.98 (s, 9H). ESI [M+H]=539.2.

Example 26 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-isopropoxyphenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 27)

To a solution of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate(30 mg, 60.5 umol, 1.0 eq.) in DMF (5 mL) was added K₂CO₃ (16.7 mg, 121umol, 2 eq.) and 2-iodopropane (20.6 mg, 121 umol, 2 eq.). The mixturewas stirred at 80° C. for 12 h, then concentrated and purified byprep-HPLC to give isopropyl(trans-4-(5-(2-(N-(tert-butypsulfamoyl)-4-isopropoxyphenyl)thiazol-2-yl)cyclohexyl)carbamate(18 mg, 33.19 umol, 55% yield, 99% purity) as a white solid. ¹H NMR (400MHz, methanol-d₄) δ=7.69 (s, 1H), 7.62 (d, J=2.6 Hz, 1H), 7.38-7.35 (m,1H), 7.14 (dd, J=2.6, 8.6 Hz, 1H), 4.84-4.78 (m, 1H), 4.70 (td, J=6.0,12.1 Hz, 1H), 3.45 (tt, J=3.9, 11.6 Hz, 1H), 3.04-2.97 (m, 1H),2.26-2.18 (m, 2H), 2.10-2.03 (m, 2H), 1.69 (dq, J=3.0, 12.8 Hz, 2H),1.46-1.38 (m, 2H), 1.36 (d, J=6.0 Hz, 6H), 1.22 (br d, J=6.2 Hz, 6H),1.09 (s, 9H). ESI [M+H]=538.2.

Example 27 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-methoxyphenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 28)

To a solution of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate (30 mg, 60.5 umol, 1.0 eq.) inDMF (4 mL) was added NaHCO₃ (10 mg, 121 umol, 2 eq.) and MeI (10.3 mg,72.6 umol, 1.2 eq.). The mixture was stirred at 60° C. for 12 h, thenconcentrated and purified by prep-HPLC (column: Welch Ultimate AQ-C18150*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 40%-70%,12min) to give isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-methoxyphenyl)thiazol-2-yl)cyclohexyl)carbamate(2.34 mg, 4.26 umol, 7% yield, 93% purity) as a pale yellow solid. ¹HNMR (400 MHz, methanol-d₄) δ=7.75-7.62 (m, 2H), 7.42 (d, J=8.4 Hz, 1H),7.20 (dd, J=2.8, 8.5 Hz, 1H), 4.84 (br d, J=5.5 Hz, 1H), 3.92 (s, 3H),3.53-3.38 (m, 1H), 3.11-2.97 (m, 1H), 2.25 (br d, J=13.1 Hz, 2H), 2.09(br d, J=10.4 Hz, 2H), 1.78-1.64 (m, 2H), 1.49-1.37 (m, 2H), 1.31-1.21(m, 6H), 1.11 (s, 9H). ESI [M+H]=510.2.

Example 28 Preparation of tert-butyl(2-(3-(N-(tert-butyl)sulfamoyl)-4-(2-(trans-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenoxy)ethyl)(methyl)carbamate (Compound 29)

A mixture of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate (140 mg, 282 umol, 1.0 eq.),tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (74 mg, 424 umol, 1.5eq.) and PPh3 (148 mg, 565 umol, 2.0 eq.) in anhydrous THF (2 mL) wasdegassed and purged with N₂ for 3 times, then DIAD (86 mg, 424 umol, 1.5eq.) was added and the mixture was stirred at 30° C. for 12 h under N₂atmosphere. The reaction mixture was concentrated and the residue waspurified prep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase:[water(10 mM NH₄HCO₃)-ACN]; B %: 40%-70%,10 min) to give tert-butyl(2-(3-(N-(tert-butyl)sulfamoyl)-4-(2-(trans-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenoxy)ethyl)(methyl)carbamate(7.58 mg, 98% purity) as a pale yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ=7.70 (br s, 2H), 7.42 (br d, J=7.9 Hz, 1H), 7.23 (br s,1H), 4.87-4.77 (m, 1H), 4.25 (br s, 2H), 3.69 (br s, 2H), 3.47 (br s,1H), 3.00 (br s, 4H), 2.25 (br d, J=11.0 Hz, 2H), 2.09 (br d, J=10.5 Hz,2H), 1.71 (br d, J=12.1 Hz, 2H), 1.54-1.35 (m, 11H), 1.25 (br d, J=5.0Hz, 6H), 1.11 (br s, 9H). ESI [M+H]=653.3.

Example 29 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-(dimethylamino)ethoxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 30)

To a solution of isopropyl(trans-4-(5-(4-(2-aminoethoxy)-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate (13 mg, 24.1 umol,1.0 eq.) in MeOH (1 mL) was added AcOH (one drop), HCHO (3.6 mg, 120.7umol, 5.0 eq.) followed by NaBH₃CN (4.5 mg, 72.4 umol, 3.0 eq.) after0.5 hr. The mixture was stirred at 25° C. for 12 h and thenconcentrated. The residue was purified by prep-HPLC (column: WelchUltimate AQ-C18 150*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN]; B%: 25%-55%,12 min) to give isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-(dimethylamino)ethoxy)phenyl)thiazol-2-yl)cyclohexyl) carbamate (20.6 mg, 99% purity, TFA salt) as awhite solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.81 (br s, 1H), 7.73 (s,1H), 7.49 (br d, J=8.3 Hz, 1H), 7.31 (br d, J=7.0 Hz, 1H), 4.86 (br d,J=5.7 Hz, 1H), 4.49 (br s, 2H), 3.68 (br s, 2H), 3.55-3.41 (m, 1H), 3.03(s, 7H), 2.25 (br d, J=11.6 Hz, 2H), 2.09 (br d, J=10.9 Hz, 2H), 1.71(q, J=12.0 Hz, 2H), 1.50-1.36 (m, 2H), 1.24 (br d, J=5.4 Hz, 6H), 1.10(s, 9H). ESI [M+H]=567.2.

Example 30 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 31)

A mixture of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-hydroxyphenyl)thiazol-2-yl)cyclohexyl)carbamate (30 mg, 60.5 umol, 1.0 eq.),1-bromo-2-methoxy-ethane (6.7 mg, 48.4 umol, 0.8 eq.) and K₂CO₃ (16.73mg, 121.05 umol, 2 eq.) in DMF (2 mL) was stirred at 30° C. for 12 hunder N₂ atmosphere. The mixture was concentrated and purified byprep-HPLC (column: Welch Ultimate AQ-C18 150×30 mm×5 um; mobile phase:[water(0.1% TFA)-ACN]; B %: 40%-70%,12 min) to give isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-methoxyethoxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate (19.84 mg, 35.70 umol, 59% yield, 99%purity) as pale yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.79 (s,1H), 7.72 (d, J=2.7 Hz, 1H), 7.42 (s, 1H), 7.26-7.20 (m, 1H), 4.87-4.74(m, 1H), 4.25 (dd, J=3.7, 5.3 Hz, 2H), 3.81 (dd, J=3.7, 5.3 Hz, 2H),3.54-3.43 (m, 4H), 33.12-3.02 (m, 1H), 2.31-2.19 (m, 2H), 2.13-2.07 (m,2H), 1.73 (br dd, J=2.8, 12.7 Hz, 2H), 1.50-1.36 (m, 2H), 1.24 (br d,J=6.2 Hz, 6H), 1.13 (s, 9H). ESI [M+H]=554.3.

Example 31 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-(methylamino)ethoxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate (Compound 32)

A solution of tert-butyl(2-(3-(N-(tert-butyl)sulfamoyl)-4-(2-(trans-4-((isopropoxycarbonyl)amino)cyclohexyl)thiazol-5-yl)phenoxy)ethyl)(methyl)carbamate(0.1 g, 153 umol, 1.0 eq.) in HCl/MeOH (4 M, 5 mL) was stirred at 20° C.for 30 mins. The reaction mixture was concentrated and purified byprep-HPLC (column: Waters Xbridge 150*25 5 u; mobile phase: [water(10 mMNH₄HCO₃)-ACN]; B %: 20%-50%,10 min) to give isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-(methylamino)ethoxy)phenyl)thiazol-2-yl)cyclohexyl)carbamate (6.84 mg, 12.25 umol, 8% yield, 99%purity) as a yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.78-7.69 (m,2H), 7.43 (d, J=8.4 Hz, 1H), 7.23 (dd, J=2.5, 8.5 Hz, 1H), 4.86-4.80 (m,1H), 4.22 (br t, J=4.8 Hz, 2H), 3.55-3.41 (m, 1H), 3.11-2.95 (m, 3H),2.50 (br s, 3H), 2.25 (br d, J=12.2 Hz, 2H), 2.09 (br d, J=10.8 Hz, 2H),1.79-1.63 (m, 2H), 1.49-1.35 (m, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.11(s, 9H). ESI [M+H]=553.2.

Example 32 Separation of oxetan-3-yltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(isobutoxymethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 34)

a) Synthesis of 4-bromo-3-(tert-butylsulfamoyl)benzoic acid

To a solution of 2-methylpropan-2-amine (2.9 g, 40.1 mmol, 3.0 eq.) inDCM (80 mL) was added 4-bromo-3-chlorosulfonyl-benzoic acid (4.0 g, 13.4mmol, 1 eq.) with THF (20 mL) at −10° C., then the mixture was stirredat 15° C. for 2 h. The reaction mixture was concentrated under reducedpressure, the residue was diluted with HCl (20 mL) and extracted withEtOAc 150 mL (50 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue which was triturated with petroleum ether yielding4-bromo-3-(tert-butylsulfamoyl)benzoic acid (4.5 g, 13.4 mmol, 100%yield) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.70 (d, J=1.98Hz, 1H), 8.03 (dd, J=8.16, 1.98 Hz, 1H) 7.63 (d, J=8.38 Hz, 1H) 1.19 (s,9H).

b) Synthesis of 2-bromo-N-tert-butyl-5-(hydroxymethyl)benzenesulfonamide

To a solution of 4-bromo-3-(tert-butylsulfamoyl)benzoic acid (3.5 g,10.4 mmol, 1 eq.) in THF (20 mL) was added BH₃-Me₂S (10 M, 12.49 mL, 12eq.) at 0° C. and stirred at 15° C. for 12 h. The reaction mixture wasquenched by addition MeOH (15 mL) at 15° C., then the reaction mixturewas concentrated under reduced pressure. The crude product was purifiedby reversed-phase HPLC (TFA condition) to yield2-bromo-N-tert-butyl-5-(hydroxymethyl)benzenesulfonamide (3g) as a whitesolid. ¹H NMR (400 MHz, methanol-d₄) δ=8.17 (d, J=2.08 Hz, 1H), 7.76 (d,J=8.07 Hz, 1H), 7.42-7.52 (m, 1H), 4.65 (s, 2H), 1.21 (s, 9H).ESI[M−H]=319.9/321.9.

c) Synthesis of 2-bromo-5-(bromomethyl)-N-tert-butyl-benzenesulfonamide

To a solution of2-bromo-N-tert-butyl-5-(hydroxymethyl)benzenesulfonamide (2.9 g, 9 mmol,1 eq.) in DCM (50 mL) was added CBr₄ (4.6 g, 13.0 mmol, 1.5 eq.) andPPh₃ (3.6 g, 13.0 mmol, 1.5 eq.) and stirred at 15° C. for 2 h. Thereaction mixture was diluted with H₂O (15 mL) and extracted with DCM 150mL (50 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, petroleum ether:ethylacetate=1:0 to 8:1 to 5:1 to 2:1 to 1:1) to yield2-bromo-5-(bromomethyl)-N-tert-butyl-benzenesulfonamide (5.1 g, 13.0mmol, quantitative yield) as a white solid. ESI[M−H]=383.8.

d) Synthesis of 2-bromo-N-tert-butyl-5-(isobutoxymethyl)benzenesulfonamide

To a solution of 2-methylpropan-1-ol (3.3 g, 45.0 mmol, 5 eq.) in DMF(15 mL) was added NaH (1.1 g, 27.0 mmol, 60% purity, 3.0 eq.) and2-bromo-5-(bromomethyl)-N-tert-butyl-benzenesulfonamide (3.5 g, 9.0mmol, 1.0 eq.). The mixture was stirred at 25° C. for 2 h.

The reaction mixture was poured into NaCl (sat.aq.) (15 mL) at 25° C.,extracted with EtOAc (30 mL), The combined organic layers were washedwith NaCl 60 mL (20 mL×3), dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by prep-HPLC (column:Welch Xtimate C18 250*50 mm*10 um; mobile phase: [water(0.1% TFA)-ACN];B %: 45%-75%,20 min) to yield2-bromo-N-tert-butyl-5-(isobutoxymethyl)benzenesulfonamide (820 mg, 2.2mmol, 24% yield) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.12(d, J=1.98 Hz, 1H), 7.74 (d, J=8.16 Hz, 1H), 7.41 (dd, J=8.16, 2.21 Hz,1H), 3.25-3.33 (m, 4H), 1.85-1.95 (m, 1H), 1.18 (s, 9H), 0.93 (d, J=6.84Hz, 6H).

e) Synthesis ofN-tert-butyl-5-(isobutoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

From 2-bromo-N-tert-butyl-5-(isobutoxymethyl)benzenesulfonamide, usingGeneral Method B. ESI[M+H]=426.2.

f) Synthesis of oxetan-3-yltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(isobutoxymethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 34)

FromN-tert-butyl-5-(isobutoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide,using General Method C. ¹H NMR (400 MHz, methanol-d₄) δ=8.15 (d, J=1.32Hz, 1H), 7.75 (s, 1H), 7.57 (dd, J=7.72, 1.32 Hz, 1H), 7.45 (d, J=7.72Hz, 1H), 5.31-5.40 (m, 1H), 4.87 (s, 1H), 4.84 (br s, 1H), 4.60 (s, 4H),3.39-3.50 (m, 1H), 3.29 (d, J=1.98 Hz, 2H), 2.98-3.06 (m, 1H), 2.24 (brd, J=12.57 Hz, 2H), 2.02-2.11 (m, 2H), 1.92 (dt, J=13.40, 6.64 Hz, 1H),1.64-1.76 (m, 2H), 1.38-1.49 (m, 2H), 1.08 (s, 9H), 0.95 (d, J=6.84 Hz,6H). ESI [M+H]=580.3.

Example 33 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(isobutoxymethyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 33)

Following the same protocol and under the same reaction conditions asfor Compound 34, Compound 33 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.06 (s, 1H), 7.67 (s, 1H), 7.48 (br d, J=7.58 Hz, 1H), 7.36 (d,J=7.70 Hz, 1H), 4.51 (s, 2H), 3.30-3.39 (m, 1H) 3.20 (br s, 3H), 2.92(tt, J=11.83, 3.03 Hz, 1H), 2.14 (br d, J=12.47 Hz, 2H), 1.98 (br d,J=11.00 Hz, 2H), 1.75-1.89 (m, 1H), 1.55-1.67 (m, 2H), 1.32 (qd,J=12.59, 2.69 Hz, 2H), 1.13 (br d, J=5.99 Hz, 6H), 1.00 (s, 9H), 0.86(d, J=6.72 Hz, 6H). ESI [M+H]=566.3.

Example 34 Preparation of isopropyltrans-N-[4-[5-[4-cyano-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 36)

a) Synthesis of 2-bromo-N-ethyl-5-nitro-benzenesulfonamide

From 1-(2-bromo-5-nitro-phenyl)sulfonyl chloride and ethylamine, usingGeneral Method G. ¹H NMR (400 MHz, methanol-d₄) δ=8.82 (d, J=2.9 Hz,1H), 8.30 (dd, J=2.6, 8.6 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 3.01 (q,J=7.3 Hz, 2H), 1.08 (t, J=7.3 Hz, 3H).

b) Synthesis of 5-amino-2-bromo-N-ethyl-benzenesulfonamide

To a solution of 2-bromo-N-ethyl-5-nitro-benzenesulfonamide (100.0 g,323.5 mmol, 1.0 eq.) in EtOH (600 mL), H₂O (200 mL) and THF (600 mL) wasadded Fe (90.3 g, 1.6 mol, 5.0 eq.) and NH₄Cl (51.9 g, 970.4 mmol, 3.0eq.). The mixture was stirred at 80° C. for 2 h and filtered. Thenconcentrated under reduced pressure, the residue diluted with H₂O (60mL) and extracted with EtOAc 1200 mL (400 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=10:1 to 0:1) to yield5-amino-2-bromo-N-ethyl-benzenesulfonamide (82.0 g, 293.7 mmol, 91%yield) as a yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.44-7.37 (m,2H), 6.74 (dd, J=2.9, 8.5 Hz, 1H), 2.95 (q, J=7.2 Hz, 2H), 1.08 (t,J=7.3 Hz, 3H). ESI [M+H]=279.0/281.0.

c) Synthesis of5-amino-N-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

From 5-amino-2-bromo-N-ethyl-benzenesulfonamide, using General Method B.¹H NMR (400 MHz, methanol-d₄) δ=7.97 (s, 1H), 7.49 (br d, J=7.94 Hz,2H), 2.98 (s, 2H), 1.35 (s, 12H), 1.00-1.08 (m, 3H). ESI [M+H]=327.3.

d) Synthesis of isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

From5-amino-N-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, using General Method C. ESI [M+H]=467.3.

e) Synthesis of isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

From isopropyl trans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate, using General Method L. ¹H NMR (400MHz, methanol-d₄) δ=8.21 (d, J=1.47 Hz, 1H), 7.78-7.86 (m, 2H), 7.44 (d,J=8.19 Hz, 1H), 4.85 (br d, J=5.87 Hz, 1H), 3.48 (ddd, J=11.43, 7.70,3.97 Hz, 1H), 3.00-3.10 (m, 1H), 2.89 (q, J=7.21 Hz, 2H), 2.22-2.30 (m,2H), 2.10 (br d, J=10.64 Hz, 2H), 1.72 (qd, J=12.76, 2.57 Hz, 2H), 1.43(qd, J=12.55, 2.93 Hz, 2H), 1.25 (br d, J=5.99 Hz, 6H), 1.04 (t, J=7.21Hz, 3H). ESI [M+H]=530.1/532.1.

f) Synthesis of isopropyltrans-N-[4-[5-[4-cyano-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 36)

A solution of isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(60 mg, 113 umol, 1 eq.), Zn(CN)₂ (27 mg, 226 umol, 2 eq.), Pd(PPh₃)₄(13 mg, 11 umol, 0.1 eq.) in NMP (2 mL) was stirred for 1 h undermicrowave at 170° C. Then diluted with H₂O (10 mL), extracted with EtOAc40 mL (20 mL×2). The combined organic layers were dried over Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1) and prep-HPLC(column: Waters Xbridge BEH C18 100*25 mm*5 um; mobile phase: [water(10mM NH₄HCO₃)-ACN]; B %: 20%-50%,10 min.) to yield isopropyltrans-N-[4-[5-[4-cyano-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(810 ug, 1 umol, 1.3% yield, 86% purity) as a yellow solid. ¹H NMR (400MHz, methanol-d₄) δ=8.40 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.87 (s, 1H),7.76-7.65 (m, 1H), 4.83 (br s, 1H), 3.55-3.39 (m, 1H), 3.14-2.99 (m,1H), 2.95-2.85 (m, 2H), 2.27 (br d, J=12.6 Hz, 2H), 2.10 (br d, J=11.7Hz, 2H), 1.79-1.67 (m, 2H), 1.50-1.37 (m, 2H), 1.25 (br d, J=6.1 Hz,6H), 1.11-0.98 (m, 3H). ESI [M+H]=477.1.

Example 35 Preparation of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[2-(isopropylamino)-2-oxo-ethyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 40)

a) Synthesis of2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]-N-isopropyl-acetamide

From 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]-N-isopropyl-acetic acidand isopropylamine, using General Method A. ¹H NMR (400 MHz,methanol-d₄) δ=7.97 (s, 1H), 7.71 (d, J=7.9 Hz, 1H), 7.37 (dd, J=2.1,8.0 Hz, 1H), 4.00-3.86 (m, 1H), 3.50 (s, 2H), 1.18 (s, 9H), 1.13 (d,J=6.6 Hz, 6H). ESI[M+H]=391.0/393.0.

b) Synthesis of2-[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-isopropyl-acetamide

From 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]-N-isopropyl-acetamide,using General Method D. ¹H NMR (400 MHz, methanol-d₄) δ=7.92 (d, J=1.1Hz, 1H), 7.66 (d, J=7.7 Hz, 1H), 7.55-7.39 (m, 1H), 3.98-3.89 (m, 1H),3.58-3.51 (m, 2H), 1.40 (s, 9H), 1.25-1.16 (m, 12H), 1.15-1.10 (m, 6H).ESI[M+H]=439.2.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[2-(isopropylamino)-2-oxo-ethyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 40)

From2-[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-isopropyl-acetamide, using General Method C. ¹H NMR (400 MHz,methanol-d₄) δ=8.11 (br s, 1H), 7.77 (s, 1H), 7.54 (br d, J=7.3 Hz, 1H),7.42 (br d, J=7.5 Hz, 1H), 4.82-4.74 (m, 1H), 4.01-3.87 (m, 1H), 3.57(br s, 2H), 3.45 (br s, 1H), 3.08-2.95 (m, 1H), 2.23 (br d, J=12.3 Hz,2H), 2.06 (br d, J=10.8 Hz, 2H), 1.78-1.61 (m, 2H), 1.49-1.33 (m, 2H),1.21 (br d, J=4.9 Hz, 6H), 1.14 (br d, J=6.4 Hz, 6H), 1.08 (s, 9H). ESI[M+H]=579.3.

Example 36 Preparation of oxetan-3-yl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(2-(isopropylamino)-2-oxoethyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 41)

Following the same protocol and under the same reaction conditions asfor Compound 40, Compound 41 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=8.05 (br d, J=7.5 Hz, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.49-7.41 (m,2H), 7.40-7.34 (m, 1H), 6.96 (s, 1H), 5.26 (quin, J=5.7 Hz, 1H), 4.73(t, J=6.8 Hz, 2H), 4.53-4.37 (m, 2H), 3.78 (qd, J=6.8, 13.6 Hz, 1H),3.47 (s, 2H), 3.29 (s, 1H), 2.98-2.84 (m, 1H), 2.13 (br d, J=12.1 Hz,2H), 1.91 (br d, J=10.1 Hz, 2H), 1.66-1.46 (m, 2H), 1.42-1.23 (m, 2H),1.03 (d, J=6.6 Hz, 6H), 1.01 (s, 9H). ESI [M+H]=593.3.

Example 37 Preparation of isopropyltrans-N-[4-[5-(2-sulfamoylphenyl)thiazol-2-yl]cyclohexyl]carbamate(Compound 44)

a) Synthesis of isopropyl trans-N-[4-[5-(2-aminophenyl)thiazol-2-yl]cyclohexyl]carbamate

From 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, usingGeneral Method C. ¹H NMR (400 MHz, methanol-d₄) δ=7.46-7.27 (m, 1H),7.21-7.06 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 6.71 (t, J=7.5 Hz, 1H), 4.82(br d, J=6.4 Hz, 1H), 3.52-3.38 (m, 1H), 2.98 (tt, J=3.5, 12.1 Hz, 1H),2.26-2.16 (m, 2H), 2.06 (br d, J=10.6 Hz, 2H), 1.68 (dq, J=2.8, 12.9 Hz,2H), 1.40 (dq, J=3.3, 12.6 Hz, 2H), 1.24-1.18 (m, 6H). ESI [M+H]=360.1.

b) Synthesis of isopropyltrans-N-[4-[5-(2-chlorosulfonylphenyl)thiazol-2-yl]cyclohexyl]carbamate

To a solution of isopropyl trans-N-[4-[5-(2-aminophenyl)thiazol-2-yl]cyclohexyl]carbamate (1.0 g, 2.8 mmol, 1.0 eq.) in H₂O (1mL) and AcOH (5 mL) was added conc. HCl (5 mL) at 0° C. followed by asolution of NaNO₂ (960 mg, 14 mmol, 5 eq.) in H₂O (1 mL), the mixturewas stirred at 0° C. for 2.5 h (mixture 1). To another mixture of CuCl₂(374 mg, 3 mmol, 1 eq.) in H₂O (4 ml) was added a solution of SO₂ inAcOH (20 mL, 2 M) and stirred at 25° C. for 1 h (mixture 2). To themixture 2 was added the mixture 1 at 0° C. The mixture was stirred at 0°C. for 0.5 h. The reaction mixture was quenched with H₂O (20 mL) at 0°C. and filtered to yield crude product isopropyltrans-N-[4-[5-(2-chlorosulfonylphenyl)thiazol-2-yl]cyclohexyl]carbamate(1.2 g, crude) as a pale yellow solid, without any purification. ESI[M+H]=443.0.

c) Synthesis of isopropyltrans-N-[4-[5-(2-sulfamoylphenyl)thiazol-2-yl]cyclohexyl]carbamate(Compound 44)

To a solution of TEA (137 mg, 1 mmol, 2 eq.), NH₃.H₂O (395 mg, 3 mmol,30% purity, 5 eq.) in THF (2 mL) was added a solution of isopropyltrans-N-[4-[5-(2-chlorosulfonylphenyl)thiazol-2-yl]cyclohexyl]carbamate(300 mg, 677 umol, 1 eq.) in THF (2 mL) at 0° C. The mixture was stirredat 20° C. for 1 h and concentrated. The residue was purified byprep-HPLC (column: Welch Ultimate AQ-C18 150*30 mm*5 um; mobile phase:[water(0.1% TFA)-ACN]; B %: 35%-65%,12 min) to yield isopropyltrans-N-[4-[5-(2-sulfamoylphenyl)thiazol-2-yl]cyclohexyl]carbamate (92mg, 216 umol, 32% yield, 99% purity) as a yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.22-8.12 (m, 1H), 7.87-7.79 (m, 1H), 7.70-7.58 (m, 2H),7.56-7.50 (m, 1H), 4.87-4.79 (m, 1H), 3.55-3.40 (m, 1H), 3.12-2.98 (m,1H), 2.32-2.18 (m, 2H), 2.14-2.01 (m, 2H), 1.79-1.65 (m, 2H), 1.50-1.35(m, 2H), 1.25 (br d, J=6.2 Hz, 6H). ESI [M+H]=424.1.

Example 38 Preparation of isopropyl(trans-4-(5-(2-(N-ethylsulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 45)

Following the same protocol and under the same reaction conditions asfor Compound 44, Compound 45 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.06 (dd, J=1.0, 7.8 Hz, 1H), 7.72 (s, 1H), 7.68-7.55 (m, 2H), 7.49(dd, J=1.0, 7.4 Hz, 1H), 4.84-4.76 (m, 1H), 3.45 (ddd, J=4.1, 7.6, 11.5Hz, 1H), 3.00 (tt, J=3.4, 12.1 Hz, 1H), 2.85 (q, J=7.3 Hz, 2H),2.31-2.17 (m, 2H), 2.12-1.98 (m, 2H), 1.69 (dq, J=2.9, 12.8 Hz, 2H),1.41 (dq, J=3.1, 12.6 Hz, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.00 (t, J=7.2Hz, 3H). ESI [M+H]=452.1.

Example 39 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 46)

Following the same protocol and under the same reaction conditions asfor Compound 44, Compound 46 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.15 (dd, J=1.3, 7.7 Hz, 1H), 7.76 (s, 1H), 7.68-7.53 (m, 2H), 7.48(dd, J=1.3, 7.5 Hz, 1H), 4.86-4.76 (m, 1H), 3.45 (tt, J=3.8, 11.5 Hz,1H), 3.02 (tt, J=3.5, 12.0 Hz, 1H), 2.30-2.17 (m, 2H), 2.12-2.01 (m,2H), 1.70 (dq, J=2.6, 12.9 Hz, 2H), 1.41 (dq, J=3.1, 12.6 Hz, 2H), 1.22(br d, J=6.2 Hz, 6H), 1.07 (s, 9H). ESI [M+H]=480.2.

Example 40 Preparation of isopropyltrans-N-[4-[5-(2-methylsulfamoylphenyl)thiazol-2-yl]cyclohexyl]carbamate(Compound 93)

Following the same protocol and under the same reaction conditions asfor Compound 44, Compound 93 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.18-7.99 (m, 1H), 7.80-7.77 (m, 1H), 7.71-7.61 (m, 2H), 7.54 (dd,J=1.2, 7.2 Hz, 1H), 4.87-4.80 (m, 1H), 3.54-3.43 (m, 1H), 3.11-2.99 (m,1H), 2.30-2.23 (m, 2H), 2.13-2.04 (m, 2H), 1.80-1.65 (m, 2H), 1.51-1.37(m, 2H), 1.25 (br d, J=6.1 Hz, 6H). ESI [M+H]=438.1.

Example 41 Preparation of oxetan-3-yltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(iso-butoxymethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 52)

a) Synthesis of 2-bromo-N-ethyl-5-(hydroxymethyl)benzenesulfonamide

To a solution of 4-bromo-3-(ethylsulfamoyl)benzoic acid (1.8 g, 5.8mmol, 1.0 eq.) in THF (40 mL) was added BH₃-Me₂S (10.0 M, 5.8 mL, 10.0eq.) at 0° C. and stirred at 25° C. for 12 h. The reaction mixture wasquenched by MeOH 50 mL at 0° C., and was stirred at 50° C. for 1 h. Thenthe reaction mixture was concentrated under reduced pressure. The crudeproduct was purified by reversed-phase HPLC (0.1% TFA condition) toyield 2-bromo-N-ethyl-5-(hydroxymethyl)benzenesulfonamide (1.2 g, 4.2mmol, 71% yield) as a yellow oil. ESI [M−H]=291.8/293.8.

b) Synthesis of [4-bromo-3-(ethylsulfamoyl)phenyl]methylmethanesulfonate

To a solution of 2-bromo-N-ethyl-5-(hydroxymethyl)benzenesulfonamide(1.1 g, 3.8 mmol, 1.0 eq) in DCM (15 mL) was added TEA (770 mg, 8 mmol,2 eq) and methanesulfonyl chloride (0.15 g, 1.31 mmol, 3.44e-1 eq.) at0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixturewas concentrated under reduced pressure. The residue was diluted withH₂O 20 mL and extracted with DCM 60 mL (20 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 0:1) to yield[4-bromo-3-(ethylsulfamoyl)phenyl]methyl methanesulfonate (600 mg, 1mmol, 42% yield) as a pale yellow solid. ESI [M−H]=369.8/371.8.

c) Synthesis of 2-bromo-N-ethyl-5-(isobutoxymethyl)benzenesulfonamide

To a solution of 2-methylpropan-1-ol (1 g, 13 mmol, 8 eq) in DMF (10 mL)was added NaH (58 mg, 1.5 mmol, 60% purity, 0.9 eq) at 0° C. The mixturewas stirred at 25° C. for 30 min. To the mixture was added a solution of[4-bromo-3-(ethylsulfamoyl)phenyl] methyl methanesulfonate (600 mg, 1.61mmol, 1 eq) in DMF (10 mL), then stirred at 25° C. for 1 h. The reactionwas quenched with sat.aq. NH₄Cl 50 mL at 0° C., extracted with EtOAc 150mL (50 mL×3). The combined organic layers were washed with sat.aq. NaCl45 mL (15 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 0:1) to yield2-bromo-N-ethyl-5-(isobutoxymethyl) benzenesulfonamide (260 mg, 742.28umol, 46% yield) as a pale yellow oil. ¹H NMR (400 MHz, methanol-d₄)δ=8.07 (d, J=1.8 Hz, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.44 (dd, J=2.0, 8.2Hz, 1H), 4.53 (s, 2H), 3.29 (br s, 2H), 2.94 (q, J=7.3 Hz, 2H), 1.90(td, J=6.6, 13.2 Hz, 1H), 1.05 (t, J=7.3 Hz, 3H), 0.94 (d, J=6.8 Hz,6H). ESI [M−H]=347.9/349.9.

d) Synthesis ofN-ethyl-5-(isobutoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

From 2-bromo-N-ethyl-5-(isobutoxymethyl)benzenesulfonamide, usingGeneral Method B. ¹H NMR (400 MHz, methanol-d₄) δ=7.76 (d, J=19.6 Hz,1H), 7.58-7.41 (m, 2H), 4.48 (d, J=3.5 Hz, 2H), 3.18 (s, 2H), 2.89-2.72(m, 2H), 1.87-1.72 (m, 1H), 1.22-1.05 (m, 12H), 0.94 (td, J=7.3, 9.1 Hz,3H), 0.84 (d, J=6.7 Hz, 6H). ESI [M+H]=398.2.

e) Synthesis of oxetan-3-yltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(isobutoxy-methyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 52)

FromN-ethyl-5-(isobutoxymethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, using General Method C. ¹H NMR (400 MHz, DMSO-d₆)δ=7.90 (s, 1H), 7.69 (s, 1H), 7.55 (br d, J=7.9 Hz, 1H), 7.49-7.38 (m,3H), 5.26 (quin, J=5.7 Hz, 1H), 4.73 (t, J=6.8 Hz, 2H), 4.56 (s, 2H),4.48-4.39 (m, 2H), 3.29 (br s, 1H), 3.23 (d, J=6.6 Hz, 2H), 2.92 (tt,J=3.3, 11.8 Hz, 1H), 2.77 (br d, J=6.8 Hz, 2H), 2.13 (br d, J=11.9 Hz,2H), 1.97-1.88 (m, 2H), 1.87-1.78 (m, 1H), 1.63-1.48 (m, 2H), 1.43-1.28(m, 2H), 0.93 (t, J=7.3 Hz, 3H), 0.88 (d, J=6.8 Hz, 6H). ESI[M+H]=552.2.

Example 42 Preparation of isopropyl(trans-4-(5-(2-(N-ethylsulfamoyl)-4-(isobutoxymethyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 51)

Following the same protocol and under the same reaction conditions asfor Compound 52, Compound 51 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.08 (s, 1H), 7.77 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.50 (d, J=7.8 Hz,1H), 4.84 (br s, 1H), 4.63 (s, 2H), 3.47 (tdd, J=3.9, 7.7, 11.4 Hz, 1H),3.33 (s, 2H), 3.04 (tt, J=3.3, 12.0 Hz, 1H), 2.89 (q, J=7.2 Hz, 2H),2.26 (br d, J=12.5 Hz, 2H), 2.13-2.05 (m, 2H), 2.01-1.88 (m, 1H), 1.72(dq, J=2.4, 12.8 Hz, 2H), 1.50-1.37 (m, 2H), 1.24 (br d, J=6.0 Hz, 6H),1.04 (t, J=7.2 Hz, 3H), 0.98 (d, J=6.7 Hz, 6H). ESI [M+H]=538.3.

Example 43 Preparation of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-cyano-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 54)

a) Synthesis of 1-(2-bromo-5-nitro-phenyl)sulfonylazetidine

From 1-(2-bromo-5-nitro-phenyl)sulfonyl chloride and azetidine, usingGeneral Method G.

b) Synthesis of 3-(azetidin-1-ylsulfonyl)-4-bromo-aniline

To a solution of 1-(2-bromo-5-nitro-phenyl)sulfonylazetidine (5.2 g,16.1 mmol, 1.0 eq.) in EtOH (30 mL), H₂O (10 mL) and THF (30 mL) wasadded Fe (4.5 g, 80.8 mmol, 5.0 eq.) and NH₄Cl (2.6 g, 48.5 mmol, 3.0eq.). The mixture was stirred at 80° C. for 12 h. The reaction mixturewas filtered. The filtrate was concentrated and the residue was dilutedwith H₂O (30 mL) and extracted with EtOAc 90 mL (30 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=10:1 to 1:10) to yield3-(azetidin-1-ylsulfonyl)-4-bromo-aniline (2.8 g, 9.6 mmol, 60% yield)as a white solid. ESI [M+H]=291.0/293.0.

c) Synthesis of3-(azetidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

A mixture of4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(11.3 g, 44.7 mmol, 5.0 eq.), 3-(azetidin-1-ylsulfonyl)-4-bromo-aniline(2.6 g, 8.9 mmol, 1.0 eq.), K₃PO₄ (9.5 g, 44.7 mmol, 5.0 eq.), Pd(PPh₃)₄(1.0 g, 893.0 umol, 0.1 eq.) in dioxane (120 mL) was stirred at 90° C.for 3 h under N₂ atmosphere. The reaction mixture was concentrated anddiluted with H₂O (30 mL) and extracted with EtOAc 90 mL (30 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=100:1 to 1:100) to yield crude3-(azetidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(3.8 g, crude) as a dark gum. ¹H NMR (400 MHz, methanol-d₄) δ=7.26 (d,J=7.9 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 6.91 (dd, J=2.1, 8.0 Hz, 1H),3.82 (t, J=7.7 Hz, 4H), 2.05 (quin, J=7.8 Hz, 2H), 1.33 (s, 12H). ESI[M+H]=339.2.

d) Synthesis of isopropyltrans-N-[4-[5-[4-amino-2-(azetidin-1-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

From3-(azetidin-1-ylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline,using General Method C. ¹H NMR (400 MHz, methanol-d₄) δ=7.59 (s, 1H),7.36 (d, J=2.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 6.89 (dd, J=2.4, 8.3 Hz,1H), 4.86-4.77 (m, 1H), 3.69 (t, J=7.6 Hz, 4H), 3.53-3.42 (m, 1H),3.07-2.93 (m, 1H), 2.28-2.17 (m, 2H), 2.16-2.11 (m, 2H), 2.08 (br d,J=7.8 Hz, 2H), 1.79-1.63 (m, 2H), 1.50-1.35 (m, 2H), 1.24 (br d, J=6.1Hz, 6H). ESI [M+H]=479.2.

e) Synthesis of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-bromo-phenyl]thiazol-2-yl]cyclohexyl]carbamate(General Method L)

To a solution of isopropyltrans-N-[4-[5-[4-amino-2-(azetidin-1-ylsulfonyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(200 mg, 418 umol, 1 eq.) in MeCN (6 mL) was added CuBr₂ (37 mg, 167umol, 0.4 eq.) and tert-butyl nitrite (64 mg, 627 umol, 1.5 eq.). Themixture was stirred at 60° C. for 1 h and concentrated. The residue wasdiluted with H₂O (5 mL) and extracted with EtOAc 60 mL (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=1:2) to yieldisopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-bromo-phenyl]thiazol-2-yl]cyclohexyl]carbamate(120 mg, 221 umol, 53% yield) as a white solid. ESI [M+H]=542.0/544.0.

f) Synthesis of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-cyano-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 54)

To a solution of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-bromo-phenyl]thiazol-2-yl]cyclohexyl]carbamate(60 mg, 110 umol, 1 eq.) in NMP (2 mL) was added Zn(CN)₂ (26 mg, 221umol, 2 eq.) and Pd(PPh₃)₄ (13 mg, 11 umol, 0.1 eq.). The mixture wasstirred at 140° C. under microwave for 1 h and filtered. The filtratewas purified by prep-HPLC (column: Nano-Micro UniSil 5-100 C18 ULTRA100*250 mm 5 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 45%-60%,10min) to yield isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-cyano-phenyl]thiazol-2-yl]cyclohexyl]carbamate(15 mg, 31 umol, 28% yield, 100% purity) as a yellow solid. ¹H NMR (400MHz, methanol-d₄) δ=8.42 (s, 1H), 8.04 (br d, J=7.83 Hz, 1H), 7.85 (s,1H), 7.75 (d, J=7.95 Hz, 1H), 4.77-4.86 (m, 1H), 3.75 (br t, J=7.64 Hz,4H), 3.44-3.53 (m, 1H), 3.03-3.16 (m, 1H), 2.26 (br d, J=12.59 Hz, 2H),2.14-2.21 (m, 2H), 2.10 (br d, J=11.98 Hz, 2H), 1.73 (br d, J=12.59 Hz,2H), 1.38-1.50 (m, 2H), 1.25 (br d, J=5.87 Hz, 6H). ESI [M+H]=489.1.

Example 44 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[2-(isopropylamino)-2-oxo-ethyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 58)

a) Synthesis of 2-(4-bromo-3-chlorosulfonyl-phenyl)acetate

HSO₃Cl (200 mL) was added slowly to a flask containing methyl2-(4-bromo-phenyl)acetate (20 g, 87 mmol, 1 eq.) was stirred at 0° C.for 5 h. The reaction mixture was quenched with ice-water (1 L) andextracted with DCM 2 L (1 L×2). The combined organic layers were washedwith H₂O (500 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield 2-(4-bromo-3-chlorosulfonyl-phenyl)acetate (30g, crude) as a yellow oil.

b) Synthesis of methyl 2-[4-bromo-3-(ethylsulfamoyl)phenyl]acetate

From 2-(4-bromo-3-chlorosulfonyl-phenyl)acetate, using General Method G.ESI[M−H]=333.8/335.8.

c) Synthesis of 2-[4-bromo-3-(ethylsulfamoyl)phenyl]acetic acid

From methyl 2-[4-bromo-3-(ethylsulfamoyl)phenyl]acetate, using GeneralMethod J. ESI[M−H]=319.9/321.9.

d) Synthesis of2-[4-bromo-3-(ethylsulfamoyl)phenyl]-N-isopropyl-acetamide

From 2-[4-bromo-3-(ethylsulfamoyl)phenyl]acetic acid and isopropylamine,using General Method A. ¹H NMR (400 MHz, methanol-d₄) δ=8.03 (d, J=2.21Hz, 1H), 7.73 (d, J=8.16 Hz, 1H), 7.39 (dd, J=2.20, 7.94 Hz, 1H), 3.94(spt, J=6.58 Hz, 1H), 3.51 (s, 2H), 2.88-2.98 (m, 2H), 1.13 (d, J=6.62Hz, 6H), 1.04 (t, J=7.28 Hz, 3H). ESI [M+H]=363.0/365.0.

e) Synthesis of2-[3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-N-isopropyl-acetamide

From 2-[4-bromo-3-(ethylsulfamoyl)phenyl]-N-isopropyl-acetamide, usingGeneral Method B. ESI [M+H]=411.1.

f) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[2-(isopropyl-amino)-2-oxo-ethyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 58)

From2-[3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl]-N-isopropyl-acetamide,using General Method C. ¹H NMR (400 MHz, methanol-d₄) δ=8.01 (d, J=1.54Hz, 1H), 7.71 (s, 1H), 7.55 (dd, J=7.72, 1.76 Hz, 1H), 7.43 (d, J=7.94Hz, 1H), 4.76-4.84 (m, 1H), 3.96 (dt, J=13.12, 6.67 Hz, 1H), 3.59 (s,2H), 3.38-3.50 (m, 1H), 2.94-3.06 (m, 1H), 2.85 (q, J=7.20 Hz, 2H),2.19-2.28 (m, 2H), 2.06 (br d, J=10.14 Hz, 2H), 1.63-1.75 (m, 2H),1.34-1.46 (m, 2H), 1.22 (br d, J=6.17 Hz, 6H), 1.15 (d, J=6.62 Hz, 6H),1.00 (t, J=7.17 Hz, 3H). ESI [M+H]=551.2.

Example 45 Preparation of oxetan-3-yl(trans-4-(5-(2-(N-ethylsulfamoyl)-4-(2-(isopropylamino)-2-oxoethyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 59)

Following the same protocol and under the same reaction conditions asfor Compound 58, Compound 59 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.01 (s, 1H), 7.71 (s, 1H), 7.55 (br d, J=7.72 Hz, 1H), 7.43 (d,J=7.72 Hz, 1H), 5.29-5.41 (m, 1H), 4.87 (br s, 2H), 4.59 (br t, J=6.06Hz, 2H), 3.96 (dt, J=13.23, 6.62 Hz, 1H), 3.59 (s, 2H), 3.39-3.51 (m,1H), 2.96-3.07 (m, 1H), 2.85 (q, J=7.28 Hz, 2H), 2.24 (br d, J=12.35 Hz,2H), 1.99-2.13 (m, 2H), 1.62-1.75 (m, 2H), 1.36-1.49 (m, 2H), 1.15 (d,J=6.62 Hz, 6H), 1.00 (t, J=7.28 Hz, 3H). ESI [M+H]=564.9.

Example 46 Preparation of oxetan-3-yl4-(5-(2-(N-ethylsulfamoyl)-4-(2-(isopropylamino)-2-oxoethyl)phenyl)thiazol-2-yl)piperazine-1-carboxylate(Compound 96)

Following the same protocol and under the same reaction conditions asfor Compound 58, Compound 96 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=7.99 (d, J=1.54 Hz, 1H), 7.52 (dd, J=7.83, 1.65 Hz, 1H), 7.42-7.46 (m,1H), 7.28 (s, 1H), 5.36-5.43 (m, 1H), 4.88 (t, J=7.17 Hz, 2H), 4.65 (dd,J=7.83, 5.40 Hz, 2H), 3.95 (dt, J=13.18, 6.53 Hz, 1H), 3.59-3.75 (m,4H), 3.51-3.58 (m, 6H), 2.86 (q, J=7.28 Hz, 2H), 1.15 (d, J=6.62 Hz,6H), 1.01 (t, J=7.17 Hz, 3H). ESI [M+H]=551.9.

Example 47 Preparation oftrans-3-(ethylsulfamoyl)-4-[2-[4-(oxetan-3-yloxy-carbonylamino)cyclohexyl]thiazol-5-yl]benzoicacid (Compound 66)

a) Synthesis of 4-bromo-3-(ethylsulfamoyl)benzoic acid

From 4-bromo-3-(chlorosulfonyl)benzoic acid, using General Method G. ¹HNMR (400 MHz, DMSO-d₆) δ=8.48 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.72 (d,J=8.2 Hz, 1H), 2.92 (quin, J=6.8 Hz, 2H), 1.00 (t, J=7.1 Hz, 3H). ESI[M−H]=305.9/307.9.

b) Synthesis of3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

From 4-bromo-3-(ethylsulfamoyl)benzoic acid, using General Method B. ESI[M−H]=354.0.

c) Synthesis oftrans-3-(ethylsulfamoyl)-4-[2-[4-(oxetan-3-yloxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoicacid (Compound 66)

From3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid andtrans-oxetan-3-yl-(-4-(5-bromothiazol-2-yl)cyclohexyl)carbamate, usingGeneral Method D. ¹H NMR (400 MHz, methanol-d₄) δ=8.63 (d, J=1.5 Hz,1H), 8.18 (dd, J=1.5, 7.9 Hz, 1H), 7.80 (s, 1H), 7.55 (d, J=7.7 Hz, 1H),5.35 (br t, J=5.6 Hz, 1H), 4.86-4.81 (m, 2H), 4.62-4.56 (m, 2H),3.51-3.38 (m, 1H), 3.10-2.98 (m, 1H), 2.91 (q, J=7.3 Hz, 2H), 2.25 (brd, J=12.6 Hz, 2H), 2.12-2.02 (m, 2H), 1.74-1.63 (m, 2H), 1.47-1.40 (m,2H), 1.04 (t, J=7.3 Hz, 3H). ESI [M+H]=510.1.

Example 48 Preparation oftrans-3-(ethylsulfamoyl)-4-[2-[4-(isopropyloxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoic acid (Compound 48)

From3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid and trans-isopropyl+4-(5-bromothiazol-2-yl)cyclohexyl)carbamate,using General Method D. ¹H NMR (400 MHz, methanol-d₄) δ=8.57 (s, 1H),8.14 (br d, J=7.9 Hz, 1H), 7.77 (br s, 1H), 7.54 (br d, J=7.7 Hz, 1H),4.74 (br s, 1H), 3.36 (br t, J=11.5 Hz, 1H), 3.03-2.89 (m, 1H), 2.80 (q,J=7.2 Hz, 2H), 2.16 (br d, J=13.0 Hz, 2H), 1.98 (br d, J=11.0 Hz, 2H),1.69-1.54 (m, 2H), 1.38-1.28 (m, 2H), 1.22-1.08 (m, 6H), 0.94 (t, J=7.3Hz, 3H). ESI [M+H]=496.1.

Example 49 Preparation of isopropyl(trans-N-(4-(5-(2-(ethylsulfamoyl)-4-((3-isopropyl-oxetan-3-yl)amino)phenyl)thiazol-2-yl)cyclohexyl))carbamate(Compound 69)

a) Synthesis of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide

To a solution of oxetan-3-one (5.0 g, 69.4 mmol, 1.0 eq.) and2-methylpropane-2-sulfinamide (10.1 g, 83.3 mmol, 1.2 eq.) in DCM (60mL) was added tetraisopropoxy-titanium (39.4 g, 138.8 mmol, 2.0 eq.).The mixture was stirred at 40° C. for 12 h. Then the reaction wasquenched with sat.aq. NaHCO₃ (30 mL) and filtered. The filtrate wasdiluted with H₂O 30 mL and extracted with DCM 60 mL (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=10:1 to 0:1) toyield 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (6.0 g, 34.2mmol, 49.3% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=5.81-5.66(m, 1H), 5.64-5.53 (m, 1H), 5.46-5.30 (m, 2H), 1.20 (s, 9H).

b) Synthesis of N-(3-isopropyloxetan-3-yl-2-methyl-propane-2-sulfinamide

To a solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (5.7g, 32.4 mmol, 1.0 eq.) in THF (100 mL) was added isopropyllithium (1.6M, 40.5 mL, 2.0 eq.) (1.6 M in hexane) under N₂ atmosphere at −78° C.The mixture was stirred at −78° C. for 45 min. The reaction mixture wasquenched with THF:AcOH=4:1 (50 mL) at −78° C., then was diluted with H₂O20 mL and extracted with EtOAc 150 mL (50 mL×3). The combined organiclayers were washed with sat.aq. NaCl 30 mL and dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC (column: Welch Xtimate C18 250*50 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %: 2%-40%,20 min) toyield N-(3-isopropyloxetan-3-yl)-2-methyl-propane-2-sulfinamide (300 mg,1.4 mmol, 4.2% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=4.86(d, J=6.8 Hz, 1H), 4.77 (d, J=6.8 Hz, 1H), 4.55 (dd, J=6.8, 11.9 Hz,2H), 3.40 (s, 1H), 2.32 (td, J=6.8, 13.7 Hz, 1H), 1.26 (s, 9H),1.09-0.91 (m, 6H)). ESI [M+H]=220.2.

c) Synthesis of 3-isopropyloxetan-3-amine (General Method E)

To a solution ofN-(3-isopropyloxetan-3-yl)-2-methyl-propane-2-sulfinamide (100 mg, 456umol, 1 eq.) in DCM (1 mL) was added HCl/EtOAc (4 M, 500 uL, 4.4 eq.).The mixture was stirred at 0° C. for 5 min, then the reaction mixturewas diluted with MTBE 3 mL then the solid was formed. The residue wasconcentrated under reduced pressure to remove solvent at 0° C. Then theresidue was triturated with MTBE:Petroleum ether=1:1 (3 mL) andfiltered, the filter cake was collected to yield3-isopropyloxetan-3-amine (20 mg, crude) which was used into the nextstep without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ=8.61 (brs, 2H), 4.58-4.46 (m, 4H), 2.20-2.10 (m, 1H), 0.94 (d, J=6.8 Hz, 6H).ESI [M+H]=116.1.

d) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-isopropyloxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 69; General Method F)

A mixture of 3-isopropyloxetan-3-amine (13 mg, 113 umol, 2 eq.),isopropylN-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(30 mg, 56 umol, 1 eq.), K₂CO₃ (23 mg, 169 umol, 3 eq.) and BrettPhos PdG3 (5 mg, 5 umol, 0.1 eq.) in t-BuOH (2 mL) was stirred at 110° C. for12 h under Ar atmosphere. The reaction mixture was concentrated underreduced pressure, then the residue was purified by prep-TLC(SiO₂,petroleum ether:ethyl acetate=2:1) and purified by prep-HPLC (column:YMC-Actus Triart C18 100*30 mm*5 um; mobile phase: [water(0.1%TFA)-ACN]; B %:25%-60%,10 min) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-isopropyloxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(1 mg, 1.9 umol, 3.3% yield, 89.8% purity) as a yellow gum. ¹H NMR (400MHz, DMSO-d₆) δ=7.53 (s, 1H), 7.34-7.22 (m, 1H), 7.11 (d, J=8.4 Hz, 1H),7.05-6.90 (m, 3H), 6.48 (dd, J=1.8, 7.9 Hz, 1H), 4.77-4.69 (m, 1H), 4.64(d, J=6.0 Hz, 2H), 4.49 (d, J=6.6 Hz, 2H), 3.26-3.23 (m, 1H), 2.86-2.79(m, 1H), 2.79-2.70 (m, 2H), 2.28-2.20 (m, 1H), 2.13-2.06 (m, 2H),1.93-1.86 (m, 2H), 1.57-1.45 (m, 2H), 1.37-1.28 (m, 2H), 1.13 (d, J=6.2Hz, 6H), 1.01-0.90 (m, 9H). ESI [M+H]=565.1.

Example 50 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-isobutyloxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 70)

a) Synthesis of N-(3-isobutyloxetan-3-yl)-2-methyl-propane-2-sulfinamide

To a solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (7.0g, 40.0 mmol, 1.0 eq.) in THF (4 mL) was added isobutyllithium (1.6 M,50.0 mL, 2.0 eq.) (1M in THF) dropwise at −78° C. under N₂ atmosphere.The mixture was stirred at −78° C. for 45 min. Then the reaction mixturewas quenched by additional THF:AcOH=4:1 (50 mL) at −78° C. and thereaction was diluted with H₂O 20 mL and extracted with EtOAc 150 mL (50mL×3). The combined organic layers were washed with sat.aq. NaCl (3 mL),and dried over Na₂SO₄, filtered and concentrated under reduced pressure.Then the residue was purified by prep-HPLC (column: Welch Xtimate C18250*50 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %:5%-48%,20 min) to yieldN-(3-isobutyloxetan-3-yl)-2-methyl-propane-2-sulfinamide (130 mg, 557umol, 1.4% yield) was obtained as a white solid. ¹H NMR (400 MHz, CDCl₃)δ=4.69 (t, J=7.0 Hz, 2H), 4.57 (d, J=6.9 Hz, 1H), 4.51 (d, J=6.6 Hz,1H), 3.56 (s, 1H), 1.95 (t, J=6.9 Hz, 1H), 1.86-1.73 (m, 2H), 1.19 (s,9H), 0.84 (d, J=6.4 Hz, 6H). ESI [M+H]=234.1.

b) Synthesis of 3-isobutyloxetan-3-amine

From N-(3-isobutyloxetan-3-yl)-2-methyl-propane-2-sulfinamide, using theconditions of General Method E. ¹H NMR (400 MHz, DMSO-d₆) δ=4.59-4.55(m, 2H), 4.54-4.50 (m, 2H), 1.84-1.74 (m, 3H), 0.92 (t, J=6.3 Hz, 2H),0.90-0.86 (m, 6H).

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-isobutyloxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 70)

From isopropylN-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 3-isobutyloxetan-3-amine, using General Method F. ¹H NMR (400 MHz,DMSO-d₆) δ=7.69-7.54 (m, 1H), 7.37 (t, J=5.6 Hz, 1H), 7.22 (d, J=8.4 Hz,1H), 7.17-7.11 (m, 1H), 7.08 (br d, J=7.3 Hz, 1H), 7.03 (d, J=1.8 Hz,1H), 6.58 (dd, J=2.1, 8.7 Hz, 1H), 4.87-4.73 (m, 1H), 4.63 (s, 4H),3.41-3.35 (m, 1H), 3.01-2.90 (m, 1H), 2.88-2.79 (m, 2H), 2.24-2.12 (m,2H), 2.06 (br d, J=7.1 Hz, 2H), 2.01-1.90 (m, 2H), 1.67-1.52 (m, 3H),1.46-1.32 (m, 2H), 1.23 (d, J=6.2 Hz, 6H), 1.03 (t, J=7.2 Hz, 3H), 0.89(d, J=6.6 Hz, 6H). ESI [M+H]=579.3.

Example 51 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-imidazol-2-ylamino)methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 73)

a) Synthesis of 4-bromo-3-(chlorosulfonyl)benzoic acid

A solution of 4-bromobenzoic acid (20.0 g, 99.5 mmol, 1.0 eq.) in HSO₃Cl(120 mL) was stirred at 100° C. for 12 h, then the reaction mixture waspoured into ice water (600 mL) slowly. The mixture was stirred for 0.5h, then filtrated to yield 4-bromo-3-chlorosulfonyl-benzoic acid (23.4g, crude) as a pale-yellow solid used directly without any purification.

b) Synthesis of methyl 4-bromo-3-chlorosulfonyl-benzoate

A solution of 4-bromo-3-chlorosulfonyl-benzoic acid (23.4 g, 78.0 mmol,1.0 eq.) in SOCl₂ (92.7 g, 780.0 mmol, 10.0 eq.) was stirred at 80° C.for 3 h. Then the mixture was concentrated under reduced pressure. Theresidue was diluted in Tol (50 mL) and MeOH (3.3 g, 101.4 mmol, 1.3eq.). The mixture was stirred at 110° C. for 2 h. Then concentratedunder reduced pressure. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 0:1) to yieldmethyl 4-bromo-3-chlorosulfonyl-benzoate (10.5 g, 33.2 mmol, 42.5%yield) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.75 (d, J=2.0Hz, 1H), 8.27 (dd, J=2.1, 8.3 Hz, 1H), 8.16 (d, J=8.3 Hz, 1H), 4.02-3.98(m, 3H).

c) Synthesis of methyl 4-bromo-3-(ethylsulfamoyl)benzoate (GeneralMethod G)

To a solution of TEA (7.8 g, 76.5 mmol, 3 eq.) in DCM (140 mL) was addedethylamine (1.3 g, 28.1 mmol, 1.1 eq.) at −20° C. Then the methyl4-bromo-3-chlorosulfonyl-benzoate (8.0 g, 25.5 mmol, 1.0 eq.) was addedbatchwise. The mixture was stirred at −20° C. for 5 min, then thereaction mixture was quenched with HCl (1M, 50 mL, pH=2) and extractedwith DCM 150 mL, the organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yield methyl4-bromo-3-(ethylsulfamoyl) benzoate (8.0 g, 24.8 mmol, 97.3% yield) as apale-yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.63 (d, J=1.8 Hz,1H), 8.10-8.00 (m, 1H), 7.93 (d, J=8.2 Hz, 1H), 3.94 (s, 3H), 2.96 (q,J=7.3 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H).

d) Synthesis of methyl3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

From methyl 4-bromo-3-(ethylsulfamoyl)benzoate, using General Method B.¹H NMR (400 MHz, methanol-d₄) δ=8.51-8.39 (m, 1H), 8.20 (dd, J=1.5, 7.7Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 3.95 (s, 3H), 2.96-2.88 (m, 2H), 1.40(s, 12H), 1.05-1.00 (m, 3H). ESI [M+H]=370.1.

e) Synthesis of methyltrans-3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoate(Compound 71)

From methyl3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzoate,using General Method D. ¹H NMR (400 MHz, methanol-d₄) δ=8.68 (d, J=1.6Hz, 1H), 8.24 (dd, J=1.8, 8.0 Hz, 1H), 7.85 (s, 1H), 7.66 (d, J=8.0 Hz,1H), 4.84 (br s, 1H), 3.99 (s, 3H), 3.48 (tt, J=3.8, 11.6 Hz, 1H), 3.05(ddd, J=3.4, 8.7, 11.9 Hz, 1H), 2.91 (q, J=7.2 Hz, 2H), 2.27 (br d,J=12.1 Hz, 2H), 2.14-2.05 (m, 2H), 1.73 (dq, J=3.0, 12.8 Hz, 2H), 1.44(dq, J=3.2, 12.6 Hz, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.05 (t, J=7.3 Hz,3H). ESI [M+H]=510.2.

f) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(hydroxy-methyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 72)

To a solution of trans-methyl3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)-cyclohexyl]thiazol-5-yl]benzoate(500 mg, 981 umol, 1 eq.) in THF (6 mL) was added LiAlH₄ (74 mg, 2 mmol,2 eq.), then stirred at 0° C. for 2 h. The reaction was quenched withH₂O 10 mL and extracted with EtOAc 30 mL (10 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography (SiO₂,Petroleum ether:Ethyl acetate=1:0 to 0:1) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(hydroxymethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(210 mg, 436 umol, 44.4% yield, 98.6% purity) as a white solid. ¹H NMR(400 MHz, methanol-d₄) δ=8.11 (s, 1H), 7.81 (s, 1H), 7.65 (d, J=7.1 Hz,1H), 7.51 (d, J=7.8 Hz, 1H), 4.85-4.80 (m, 1H), 4.75 (s, 2H), 3.48 (ddd,J=3.6, 7.7, 11.6 Hz, 1H), 3.14-3.01 (m, 1H), 2.90 (q, J=7.3 Hz, 2H),2.28 (br d, J=12.0 Hz, 2H), 2.15-2.07 (m, 2H), 1.80-1.66 (m, 2H),1.52-1.38 (m, 2H), 1.25 (br d, J=6.0 Hz, 6H), 1.04 (t, J=7.2 Hz, 3H).ESI [M+H]=482.1.

g) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-formyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate

To a solution of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(hydroxymethyl)-phenyl]thiazol-2-yl]cyclohexyl]carbamate(100 mg, 207 umol, 1 eq.) in CHCl₃ (1 mL)/MeOH (1 mL) was added MnO₂(361 mg, 4 mmol, 20 eq.). The mixture was stirred at 60° C. for 2 h. Thereaction mixture was filtered, and the filtrate was concentrated underreduced pressure. The residue was purified by prep-TLC (SiO₂, petroleumether:ethyl acetate=1:2) to yield isopropyltrans-N-[4-[5-[2-(ethyl-sulfamoyl)-4-formyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(30 mg, 62.55 umol, 30.13% yield) as a white solid. ESI [M+H]=480.2.

h) Synthesis ofisopropyl-trans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]amino]methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(General Method H)

To a mixture of 1-(2-trimethylsilylethoxymethyl)imidazol-2-amine (20 mg,94 umol, 1.5 eq.) and isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-formyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(30 mg, 62 umol, 1 eq.) in DCM (1 mL) was added Ti(i-PrO)₄ (35 mg, 125umol, 37 uL, 2 eq.) and Et₃N (633 ug, 6 umol, 0.1 eq.), then the mixturewas stirred at 25° C. for 16 h under N₂ atmosphere. The mixture wasadded NaBH₄ (3.6 mg, 93.9 umol, 1.5 eq.) at 0° C., and stirred at 25° C.for 2 h. The reaction mixture was quenched with H₂O 10 mL at 25° C. andconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[[1-(2-trimethylsilylethoxy-methyl)imidazol-2-yl]amino]methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(50 mg, crude) as a yellow oil. ESI [M+H]=677.3.

i) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-imidazol-2-ylamino)methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 73; General Method I)

A mixture of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[[1-(2-trimethylsilyl-ethoxymethyl)imidazol-2-yl]amino]methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(50 mg, 74 umol, 1 eq.) in TFA (1 mL) and DCM (1 mL) was stirred at 20°C. for 1 h. The reaction mixture was concentrated under reduced pressureto remove DCM at 25° C. The residue was diluted with EtOH (1 mL) andstirred at 60° C. for 3 h. The mixture was concentrated under reducedpressure. The residue was purified by prep-HPLC (TFA condition).(column: Welch Ultimate AQ-C18 150*30 mm*5 um; mobile phase: [water(0.1%TFA)-ACN]; B %: 18%-48%,12 min) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-imidazol-2-ylamino)methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(9 mg, 13 umol, 18% yield, 100% purity, TFA) as a pale yellow solid. ¹HNMR (400 MHz, methanol-d₄) δ=8.08 (d, J=1.1 Hz, 1H), 7.74 (s, 1H), 7.64(dd, J=1.4, 7.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 6.88 (s, 2H), 4.85-4.74(m, 1H), 4.65 (s, 2H), 3.51-3.37 (m, 1H), 3.08-2.96 (m, 1H), 2.81 (q,J=7.3 Hz, 2H), 2.33-2.18 (m, 2H), 2.07 (br d, J=10.4 Hz, 2H), 1.69 (dq,J=3.0, 12.8 Hz, 2H), 1.41 (dq, J=3.1, 12.6 Hz, 2H), 1.22 (br d, J=6.2Hz, 6H), 0.97 (t, J=7.3 Hz, 3H). ESI [M+H]=547.1.

Example 52 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(oxazol-2-ylamino)methyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 74)

From isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-formyl-phenyl]thiazol-2-yl]cyclohexyl]carbamateand 2-amino oxazole, using General Method H. ¹H NMR (400 MHz,methanol-d₄) δ=8.04 (s, 1H), 7.72 (s, 1H), 7.64-7.55 (m, 1H), 7.46 (d,J=7.7 Hz, 1H), 7.32 (d, J=1.1 Hz, 1H), 6.76 (d, J=0.9 Hz, 1H), 4.60 (brs, 1H), 4.56 (s, 2H), 3.53-3.39 (m, 1H), 3.06-2.94 (m, 1H), 2.84 (q,J=7.3 Hz, 2H), 2.29-2.18 (m, 2H), 2.07 (br d, J=9.9 Hz, 2H), 1.77-1.60(m, 2H), 1.50-1.36 (m, 2H), 1.23 (br d, J=6.2 Hz, 6H), 1.00 (t, J=7.2Hz, 3H). ESI [M+H]=548.3.

Example 53 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 75)

To a solution of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-formyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(30 mg, 62 umol, 1 eq.) in EtOH (1 mL) was added oxaldehyde (27 mg, 187umol, 24 uL, 3 eq.) (40% aq.) and NH₃.H₂O (146 mg, 1.3 mmol, 30% purity,20 eq.) at 0° C. The mixture was stirred at 25° C. for 2 h, andconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Welch Ultimate AQ-C18 150*30 mm*5 um; mobile phase:[water(0.1% TFA)-ACN]; B %: 30%-60%,12 min) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-yl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(16 mg, 25 umol, 40% yield, 99.3% purity, TFA) as a yellow solid. ¹H NMR(400 MHz, methanol-d₄) δ=8.70 (d, J=2.0 Hz, 1H), 8.15 (dd, J=2.0, 8.2Hz, 1H), 7.86 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.72 (s, 2H), 4.83-4.78(m, 1H), 3.45 (tdd, J=4.0, 7.6, 11.7 Hz, 1H), 3.04 (tt, J=3.5, 12.0 Hz,1H), 2.87 (q, J=7.3 Hz, 2H), 2.26 (br d, J=12.1 Hz, 2H), 2.12-2.03 (m,2H), 1.77-1.65 (m, 2H), 1.48-1.36 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H),1.05-0.92 (m, 3H). ESI [M+H]=518.0.

Example 54 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylmethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 78)

a) Synthesis of methyl2-[3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate

From methyl 2-(4-bromo-3-(N-ethylsulfamoyl)phenyl)acetate, using GeneralMethod B. ¹H NMR (400 MHz, DMSO-d₆) δ=7.97-7.83 (m, 1H), 7.70 (s, 1H),7.51-7.44 (m, 2H), 3.81 (s, 2H), 3.64-3.58 (m, 3H), 2.88-2.75 (m, 2H),1.29 (s, 12H), 0.93 (t, J=7.2 Hz, 3H). ESI [M+H]=384.1.

b) Synthesis of methyltrans-2-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]acetate(Compound 76)

From methyl2-[3-(ethylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetateand isopropyl (trans-4-(5-bromothiazol-2-yl)cyclohexyl)carbamate, usingGeneral Method D. ¹H NMR (400 MHz, methanol-d₄) δ=8.02 (d, J=1.4 Hz,1H), 7.75 (s, 1H), 7.58 (dd, J=1.6, 7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H),4.82 (br s, 1H), 3.84 (s, 2H), 3.74 (s, 3H), 3.47 (tt, J=3.8, 11.5 Hz,1H), 3.35-3.35 (m, 1H), 2.89 (q, J=7.3 Hz, 2H), 2.31-2.21 (m, 2H),2.14-2.03 (m, 2H), 1.72 (dq, J=2.8, 12.9 Hz, 2H), 1.43 (dq, J=3.1, 12.5Hz, 2H), 1.24 (br d, J=6.1 Hz, 6H), 1.04 (t, J=7.3 Hz, 3H). ESI[M+H]=524.2.

c) Synthesis oftrans-2-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonyl-amino)cyclohexyl]thiazol-5-yl]phenyl]aceticacid (Compound 77; General Method J)

To a solution of methyltrans-2-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxy-carbonylamino)cyclohexyl]thiazol-5-yl]phenyl]acetate(800 mg, 1.5 mmol, 1 eq.) in MeOH (8 mL), H₂O (4 mL) was added LiOH (110mg, 4.5 mmol, 3 eq.). The mixture was stirred at 50° C. for 2 h. Themixture was concentrated under reduced pressure. The residue wasadjusted pH=2 with HCl (6M) and extracted with EtOAc 40 mL (20 mL×2).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to yieldtrans-2-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonyl-amino)cyclohexyl]thiazol-5-yl]phenyl]acetic acid (750 mg, crude) as a yellowoil. ¹H NMR (400 MHz, methanol-d₄) δ=8.00 (s, 1H), 7.74 (s, 1H), 7.56(br d, J=7.9 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 4.89-4.88 (m, 1H), 3.76(s, 2H), 3.45 (br t, J=11.0 Hz, 1H), 3.01 (br t, J=12.2 Hz, 1H), 2.87(q, J=7.2 Hz, 2H), 2.24 (br d, J=12.1 Hz, 2H), 2.07 (br d, J=10.4 Hz,2H), 1.77-1.62 (m, 2H), 1.48-1.33 (m, 2H), 1.22 (br d, J=6.0 Hz, 6H),1.01 (t, J=7.3 Hz, 3H). ESI [M+H]=510.2.

d) Synthesis of isopropyltrans-N-[4-[5-[4-[2-(2,2-dimethoxyethylamino)-2-oxo-ethyl]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

Fromtrans-2-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]aceticacid and 2,2-dimethoxyethanamine, using General Method A. ESI[M+H]=597.3.

e) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylmethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 78)

A solution of isopropyltrans-N-[4-[5-[4-[2-(2,2-dimethoxyethylamino)-2-oxo-ethyl]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(60 mg, 100 umol, 1 eq.) and NH₄OAc (16 mg, 201 umol, 2 eq.) in AcOH (2mL) was heated at 100° C. for 30 min under microwave. The mixture wasconcentrated, then the residue was purification by prep-TLC (petroleumether:ethyl acetate=0:1) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylmethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(2 mg, 3.4 umol, 3.4% yield, 91.2% purity) as pale yellow solid. ¹H NMR(400 MHz, methanol-d₄) δ=8.02 (s, 1H), 7.73 (s, 1H), 7.47-7.61 (m, 4H),4.67-4.77 (m, 1H), 4.51 (s, 2H), 3.44 (br s, 1H), 3.01 (s, 1H),2.75-2.88 (m, 2H), 2.24 (br d, J=14.99 Hz, 2H), 2.02 (br d, J=18.52 Hz,2H), 1.60-1.82 (m, 2H), 1.33-1.51 (m, 2H), 1.22 (br d, J=6.17 Hz, 6H),0.92-1.05 (m, 3H). ESI [M+H]=532.2.

Example 55 Preparation of isopropyltrans-N-[4-[5-[4-[2-(benzylamino)-2-oxo-ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 79)

Fromtrans-2-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonylamino)cyclohexyl]thiazol-5-yl]phenyl]aceticacid and benzylamine, using General Method A. ¹H NMR (400 MHz,methanol-d₄) δ=8.04 (s, 1H), 7.79 (s, 1H), 7.58 (br d, J=7.5 Hz, 1H),7.45 (d, J=7.7 Hz, 1H), 7.34-7.18 (m, 5H), 4.87-4.77 (m, 1H), 4.38 (s,2H), 3.69 (s, 2H), 3.45 (br t, J=11.8 Hz, 1H), 3.11-2.97 (m, 1H), 2.84(q, J=7.3 Hz, 2H), 2.24 (br d, J=12.8 Hz, 2H), 2.07 (br d, J=10.4 Hz,2H), 1.78-1.62 (m, 2H), 1.50-1.32 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H),1.00 (t, J=7.3 Hz, 3H). ESI [M+H]=599.2

Example 56 Preparation of isopropyltrans-N-[4-[5-[4-[2-(isopropyl(methyl)amino)-2-oxo-ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 80)

Following the same General Method A, Compound 80 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=7.96 (br d, J=3.1 Hz, 1H), 7.80 (s, 1H),7.57-7.50 (m, 1H), 7.49-7.44 (m, 1H), 4.84-4.75 (m, 1H), 4.27 (td,J=6.7, 13.1 Hz, 1H), 3.95 (s, 1H), 3.89 (s, 1H), 3.45 (br t, J=11.7 Hz,1H), 3.05 (br t, J=12.0 Hz, 1H), 2.93 (s, 2H), 2.86 (q, J=7.3 Hz, 2H),2.81 (s, 1H), 2.25 (br d, J=12.6 Hz, 2H), 2.07 (br d, J=11.2 Hz, 2H),1.78-1.63 (m, 2H), 1.48-1.34 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.17(d, J=6.6 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H), 1.01 (t, J=7.2 Hz, 3H). ESI[M+H]=565.3.

Example 57 Preparation of isopropyltrans-N-[4-[5-[4-[2-(benzyl(methyl)amino)-2-oxo-ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 81)

Following the same General Method A, Compound 81 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=8.01 (s, 0.5H), 7.93 (s, 0.5H), 7.82-7.76 (m,1H), 7.59-7.53 (m, 1H), 7.47 (br d, J=7.3 Hz, 1H), 7.37-7.29 (m, 2H),7.28-7.22 (m, 2H), 7.15 (br d, J=7.3 Hz, 1H), 4.83-4.77 (m, 1H), 4.72(s, 1H), 4.62 (s, 1H), 4.03-3.93 (m, 2H), 3.45 (br t, J=11.6 Hz, 1H),3.10-3.00 (m, 3H), 2.96 (s, 1H), 2.90-2.77 (m, 2H), 2.24 (br d, J=12.3Hz, 2H), 2.07 (br d, J=11.7 Hz, 2H), 1.71 (q, J=12.3 Hz, 2H), 1.41 (q,J=11.8 Hz, 2H), 1.22 (br d, J=5.7 Hz, 6H), 1.00 (t, J=7.1 Hz, 3H). ESI[M+H]=613.2.

Example 58 Preparation of isopropyltrans-N-[4-[5-[4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 82)

Following the same General Method A, Compound 82 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=7.97 (s, 1H), 7.79 (s, 1H), 7.56-7.52 (m, 1H),7.48-7.44 (m, 1H), 4.83 (br s, 1H), 3.85 (s, 2H), 3.58 (t, J=6.7 Hz,2H), 3.45 (br t, J=6.8 Hz, 3H), 3.05 (br t, J=12.1 Hz, 1H), 2.87 (q,J=7.3 Hz, 2H), 2.24 (br d, J=12.6 Hz, 2H), 2.12-2.03 (m, 2H), 2.03-1.96(m, 2H), 1.94-1.86 (m, 2H), 1.80-1.63 (m, 2H), 1.49-1.33 (m, 2H), 1.22(br d, J=6.0 Hz, 6H), 1.02 (t, J=7.3 Hz, 3H). ESI [M+H]=563.2.

Example 59 Preparation of isopropyltrans-N-[4-[5-[4-[2-oxo-2-(piperidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 83)

Following the same General Method A, Compound 83 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=7.96 (s, 1H), 7.73 (s, 1H), 7.50-7.56 (m, 1H),7.41-7.47 (m, 1H), 4.76-4.84 (m, 1H), 3.91 (s, 2H), 3.56 (dt, J=14.17,5.49 Hz, 4H), 3.40-3.49 (m, 1H), 2.97-3.06 (m, 1H), 2.85 (q, J=7.28 Hz,2H), 2.24 (br d, J=12.57 Hz, 2H), 2.02-2.11 (m, 2H), 1.61-1.75 (m, 4H),1.46-1.59 (m, 4H), 1.35-1.45 (m, 2H), 1.22 (br d, J=5.95 Hz, 6H), 1.01(t, J=7.28 Hz, 3H). ESI [M+H]=577.3.

Example 60 Preparation of isopropyltrans-N-[4-[5-[4-[2-oxo-2-(morpholin-4-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 84)

Following the same General Method A, Compound 84 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=7.96 (s, 1H), 7.79 (s, 1H), 7.51-7.57 (m, 1H),7.43-7.49 (m, 1H), 4.80-4.86 (m, 1H), 3.93 (s, 2H), 3.57-3.70 (m, 8H),3.40-3.51 (m, 1H), 2.98-3.09 (m, 1H), 2.86 (q, J=7.13 Hz, 2H), 2.21-2.29(m, 2H), 2.07 (br d, J=11.69 Hz, 2H), 1.65-1.77 (m, 2H), 1.35-1.48 (m,2H), 1.17-1.26 (m, 6H), 1.01 (t, J=7.17 Hz, 3H). ESI [M+H]=579.3.

Example 61 Preparation of isopropyltrans-N-[4-[5-[4-[2-oxo-2-(3-hydroxyazetidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 85)

Following the same General Method A, Compound 85 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=8.00 (d, J=1.5 Hz, 1H), 7.90 (s, 1H), 7.62-7.56(m, 1H), 7.54-7.48 (m, 1H), 4.79-4.75 (m, 1H), 4.62 (tt, J=4.3, 6.7 Hz,1H), 4.57-4.48 (m, 1H), 4.25 (dd, J=7.9, 10.6 Hz, 1H), 4.10-4.04 (m,1H), 3.80 (dd, J=4.2, 10.6 Hz, 1H), 3.73-3.64 (m, 2H), 3.49 (tt, J=3.9,11.6 Hz, 1H), 3.19-3.09 (m, 1H), 2.92 (q, J=7.2 Hz, 2H), 2.29 (br d,J=12.5 Hz, 2H), 2.11 (br d, J=10.0 Hz, 2H), 1.75 (dq, J=3.1, 12.8 Hz,2H), 1.52-1.38 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.06 (t, J=7.3 Hz,3H). ESI [M+H]=565.2.

Example 62 Preparation of isopropyltrans-N-[4-[5-[4-[2-amino-2-oxo-ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 86)

Following the same General Method A, Compound 86 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=8.05 (d, J=1.6 Hz, 1H), 7.80 (s, 1H), 7.64-7.58(m, 1H), 7.48 (d, J=7.9 Hz, 1H), 4.88-4.87 (m, 1H), 3.68 (s, 2H),3.52-3.42 (m, 1H), 3.17-3.00 (m, 1H), 2.90 (q, J=7.3 Hz, 2H), 2.27 (brd, J=12.1 Hz, 2H), 2.10 (br d, J=10.3 Hz, 2H), 1.80-1.66 (m, 2H),1.50-1.38 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.04 (t, J=7.2 Hz, 3H).ESI [M+H]=509.2.

Example 63 Preparation of isopropyltrans-N-[4-[5-[4-[2-oxo-2-(azetidin-1-yl)ethyl]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 87)

Following the same General Method A, Compound 87 was prepared. ¹H NMR(400 MHz, methanol-d₄) δ=7.99 (d, J=1.6 Hz, 1H), 7.81 (s, 1H), 7.57 (dd,J=1.8, 7.9 Hz, 1H), 7.52-7.45 (m, 1H), 4.89-4.88 (m, 1H), 4.34 (t, J=7.7Hz, 2H), 4.06 (t, J=7.8 Hz, 2H), 3.65 (s, 2H), 3.48 (tt, J=3.9, 11.6 Hz,1H), 3.08 (tt, J=3.4, 12.0 Hz, 1H), 2.90 (q, J=7.3 Hz, 2H), 2.41-2.32(m, 2H), 2.30-2.23 (m, 2H), 2.15-2.06 (m, 2H), 1.73 (dq, J=2.9, 12.9 Hz,2H), 1.51-1.37 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.05 (t, J=7.2 Hz,3H). ESI [M+H]=549.2.

Example 64 Preparation of isopropyltrans-N-[4-[5-(4-(methylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate(Compound 89)

a) Synthesis of 1-(2-bromo-5-nitro-phenyl)sulfonylpyrrolidine

From 2-bromo-5-nitrobenzenesulfonyl chloride General Method G. ¹H NMR(400 MHz, methanol-d₄) δ=8.81 (d, J=2.69 Hz, 1H), 8.33 (dd, J=8.68, 2.69Hz, 1H), 8.13 (d, J=8.68 Hz, 1H), 3.44-3.49 (m, 4H), 1.97 (dt, J=6.48,3.48 Hz, 4H).

b) Synthesis of 4-bromo-3-pyrrolidin-1-ylsulfonyl-aniline

A mixture of 1-(2-bromo-5-nitro-phenyl)sulfonylpyrrolidine (3.0 g, 9.0mmol, 1.0 eq.), NH₄Cl (1.4 g, 27.0 mmol, 3.0 eq.), Fe (2.5 g, 45.0 mmol,5.0 eq.) in THF (30 mL), EtOH (30 mL) and H₂O (10 mL) was stirred at 80°C. for 4 h. The reaction mixture was filtered, and the filtrate wasconcentrated. The residue was diluted with H₂O (10 mL) and extractedwith EtOAc 150 mL (50 mL×3). The combined organic layers dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography (SiO₂, Petroleum ether:Ethylacetate=10:1 to 1:1 to 0:1) to yield4-bromo-3-pyrrolidin-1-ylsulfonyl-aniline (2.3 g, 7.5 mmol, 84% yield)as a white solid. ESI [M+H]=304.9/306.9.

c) Synthesis of3-pyrrolidin-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

From 4-bromo-3-pyrrolidin-1-ylsulfonyl-aniline, using General Method B.¹H NMR (400 MHz, DMSO-d₆) δ=7.13-7.04 (m, 1H), 6.96 (s, 1H), 6.80-6.70(m, 1H), 3.16 (br t, J=6.3 Hz, 4H), 1.67-1.62 (m, 4H), 1.25 (s, 12H).ESI [M+H]=353.1.

d) Synthesis of isopropyltrans-N-[4-[5-(4-amino-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate(Compound 88)

From3-pyrrolidin-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline,using General Method D. ¹H NMR (400 MHz, methanol-d₄) δ=7.78-7.66 (m,1H), 7.41 (br s, 1H), 7.24 (br d, J=8.2 Hz, 1H), 7.00-6.90 (m, 1H),4.87-4.77 (m, 1H), 3.45 (br t, J=11.7 Hz, 1H), 3.12-3.05 (m, 1H), 3.01(br t, J=6.1 Hz, 4H), 2.20 (br d, J=12.1 Hz, 2H), 2.07 (br d, J=10.6 Hz,2H), 1.86-1.75 (m, 4H), 1.74-1.61 (m, 2H), 1.48-1.34 (m, 2H), 1.22 (brd, J=6.0 Hz, 6H). ESI [M+H]=493.2.

e) Synthesis of isopropyltrans-N-[4-[5-(4-(methylamino)-2-pyrrolidin-1-ylsulfonyl-phenynthiazol-2-yl]cyclohexyl]carbamate(Compound 89)

A mixture of isopropyltrans-N-[4-[5-(4-amino-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate (170 mg, 345 umol, 1 eq.), TFA (4 mg,35 umol, 0.1 eq.) in diethoxymethoxyethane (2 mL) was stirred at 100° C.for 12 h. The mixture was concentrated followed by addition of EtOH (1mL) and NaBH₄ (39 mg, 1 mmol, 3 eq.) at 0° C. The mixture was stirred at80° C. for 2 h and quenched by H₂O (2 mL) and extracted with EtOAc 10 mL(5 mL×2). The combined organic layers were washed with H₂O (5 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (column: Welch UltimateAQ-C18 150*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN]; B %:40%-70%,12 min) to yield isopropyltrans-N-[4-[5-(4-(methylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate(34 mg, 64 umol, 19% yield, 92% purity) as a yellow solid. ¹H NMR (400MHz, methanol-d₄) δ=7.67 (s, 1H), 7.29-7.19 (m, 2H), 6.80 (dd, J=2.2,8.4 Hz, 1H), 4.83 (br s, 1H), 3.45 (br t, J=11.6 Hz, 1H), 3.09-3.02 (m,1H), 2.99 (br t, J=6.4 Hz, 4H), 2.83 (s, 3H), 2.20 (br d, J=12.1 Hz,2H), 2.07 (br d, J=11.2 Hz, 2H), 1.78 (br t, J=6.5 Hz, 4H), 1.75-1.61(m, 2H), 1.47-1.34 (m, 2H), 1.22 (br d, J=6.0 Hz, 6H). ESI [M+H]=507.2.

Example 65 Preparation of isopropyltrans-N-[4-[5-[4-(1H-imidazol-2-ylamino)-2-sulfamoyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 90; General Method K)

To a solution of isopropyltrans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (200 mg, 404 umol, 1 eq.) inn-BuOH (4 mL) was added TsOH (209 mg, 1 mmol, 3 eq.) and2-bromo-1H-imidazole (297 mg, 2 mmol, 5 eq.). The mixture was stirred at140° C. for 12 h. The reaction mixture was concentrated under reducedpressure and purified by prep-HPLC (column: Waters Xbridge BEH C18100*30 mm*10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 30%-90%, 10min) to yield isopropyltrans-N-[4-[5-[4-(1H-imidazol-2-ylamino)-2-sulfamoyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(12 mg, 20 umol, 40% yield, 100% purity, TFA) as a yellow solid. ¹H NMR(400 MHz, methanol-d₄) δ=7.97 (d, J=2.0 Hz, 1H), 7.80-7.74 (m, 1H),7.58-7.52 (m, 1H), 7.51-7.45 (m, 1H), 7.10 (s, 2H), 4.83-4.76 (m, 1H),3.45 (br t, J=11.6 Hz, 1H), 3.09-2.96 (m, 1H), 2.24 (br d, J=12.8 Hz,2H), 2.11-1.96 (m, 2H), 1.83-1.64 (m, 2H), 1.47-1.32 (m, 2H), 1.22 (brd, J=6.0 Hz, 6H). ESI [M+H]=505.1.

Example 66 Preparation of isopropyltrans-N-[4-[5-[2-(dimethylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 91)

a) Synthesis of 2-bromo-N,N-dimethyl-5-nitro-benzenesulfonamide

From 2-bromo-5-nitrobenzenesulfonyl chloride and dimethylamine, usingGeneral Method G. ESI [M+H]=308.9/310.9.

b) Synthesis of 5-amino-2-bromo-N,N-dimethyl-benzenesulfonamide

To a solution of 2-bromo-N,N-dimethyl-5-nitro-benzenesulfonamide (4.6 g,14.8 mmol, 1.0 eq.) in H₂O (20 mL), EtOH (60 mL) and THF (60 mL) wasadded Fe (4.1 g, 74.1 mmol, 5.0 eq.) and NH₄Cl (2.4 g, 44.5 mmol, 3.0eq.). The mixture was stirred at 80° C. for 2 h then filtered, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with H₂O (20 mL) and extracted with EtOAc 90 mL (30 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=1:0 to 0:1) to yield5-amino-2-bromo-N,N-dimethyl-benzenesulfonamide (3.9 g, 14.0 mmol, 94%yield) as a pale yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.43 (d,J=8.6 Hz, 1H), 7.35 (d, J=2.8 Hz, 1H), 6.75 (dd, J=2.8, 8.6 Hz, 1H),2.86 (s, 6H). ESI [M+H]=278.9/281.0.

c) Synthesis of 2-bromo-5-(1H-imidazol-2-ylamino)-N,N-dimethyl-benzenesulfonamide

From 5-amino-2-bromo-N,N-dimethyl-benzenesulfonamide, using GeneralMethod K. ¹H NMR (400 MHz, methanol-d₄) δ=7.97-7.84 (m, 2H), 7.41 (dd,J=2.8, 8.5 Hz, 1H), 7.12 (s, 2H), 2.93 (s, 6H). ESI [M+H]=345.0/347.0.

d) Synthesis of 5-(1H-imidazol-2-ylamino)-N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

A solution of2-bromo-5-(1H-imidazol-2-ylamino)-N,N-dimethyl-benzenesulfonamide (380mg, 1 mmol, 1 eq.),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.4 g, 5.5 mmol, 5.0 eq.), [2-(2-aminophenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane (74 mg, 110 umol, 0.1 eq.), DIEA (711mg, 6 mmol, 5 eq.) in MeOH (10 mL) was stirred at 50° C. for 12 h underN₂ atmosphere. The reaction mixture was concentrated and purified bycolumn chromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to THF)to yield5-(1H-imidazol-2-ylamino)-N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)benzenesulfonamide(300 mg, crude) as a brown oil. ¹H NMR (400 MHz, methanol-d₄)δ=7.53-7.40 (m, 1H), 7.39-7.31 (m, 1H), 7.29-7.14 (m, 1H), 6.92 (s, 1H),6.82 (d, J=2.4 Hz, 1H), 3.72 (td, J=6.6, 13.2 Hz, 3H), 3.22 (q, J=7.5Hz, 3H), 1.38-1.36 (m, 12H). ESI [M+H]=393.1.

e) Synthesis of isopropyltrans-N-[4-[5-[2-(dimethylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 91)

From5-(1H-imidazol-2-ylamino)-N,N-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)benzenesulfonamide,using General Method D. ¹H NMR (400 MHz, methanol-d₄) δ=7.90 (d, J=2.3Hz, 1H), 7.72 (s, 1H), 7.62-7.51 (m, 2H), 7.14 (s, 2H), 4.84-4.78 (m,1H), 3.47 (tt, J=3.9, 11.6 Hz, 1H), 3.05 (tt, J=3.5, 12.0 Hz, 1H),2.65-2.55 (m, 6H), 2.32-2.18 (m, 2H), 2.14-2.03 (m, 2H), 1.71 (dq,J=2.9, 12.8 Hz, 2H), 1.44 (dq, J=3.3, 12.5 Hz, 2H), 1.25 (br d, J=6.3Hz, 6H). ESI [M+H]=533.2.

Example 67 Preparation of isopropyltrans-N-[4-[5-[4-(1H-imidazol-2-ylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 92)

a) Synthesis ofN-(4-bromo-3-pyrrolidin-1-ylsulfonyl-phenyl)-1H-imidazol-2-amine

From 4-bromo-3-(pyrrolidin-1-ylsulfonyl)aniline, using General Method K.¹H NMR (400 MHz, methanol-d₄) δ=7.82-7.92 (m, 2H), 7.38 (dd, J=8.49,2.76 Hz, 1H), 7.06-7.11 (m, 2H), 3.36-3.48 (m, 4H), 1.93 (dt, J=6.45,3.50 Hz, 4H). ESI [M+H]=370.9/372.9.

b) Synthesis ofN-[3-pyrrolidin-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-imidazol-2-amine

A mixture of4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(654 mg, 3 mmol, 5 eq.),N-(4-bromo-3-pyrrolidin-1-ylsulfonyl-phenyl)-1H-imidazol-2-amine (250mg, 515 umol, 1 eq., TFA), [2-(2-amino-phenyl)phenyl]-chloro-palladium;bis(1-adamantyl)-butyl-phosphane (34 mg, 52 umol, 0.1 eq.), DIEA (333mg, 3 mmol, 5 eq.) in MeOH (15 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 50° C. for 12 h under N₂atmosphere. The reaction mixture was concentrated and purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=1:0 to 5:1 to 1:1 to0:1) to yieldN-[3-pyrrolidin-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-imidazol-2-amine(190 mg, 454 umol, 88% yield) as a white solid. ESI [M+H]=419.2.

c) Synthesis of isopropyltrans-N-[4-[5-[4-(1H-imidazol-2-ylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 92)

FromN-[3-pyrrolidin-1-ylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-imidazol-2-amine, using General Method D. ¹H NMR (400 MHz,methanol-d₄) δ=7.91 (d, J=1.75 Hz, 1H), 7.76 (br s, 1H), 7.50-7.59 (m,2H), 7.13 (s, 2H), 4.82 (br d, J=6.00 Hz, 1H), 3.46 (br t, J=11.57 Hz,1H), 3.04 (br s, 1H), 2.97 (br t, J=6.25 Hz, 4H), 2.21 (br d, J=12.63Hz, 2H), 2.07 (br d, J=10.88 Hz, 2H), 1.78 (br t, J=6.25 Hz, 4H), 1.69(br d, J=12.01 Hz, 2H), 1.38-1.48 (m, 2H), 1.23 (br d, J=6.13 Hz, 6H).ESI [M+H]=559.2.

Example 68 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylcarbamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 94)

a) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[1-(2-trimethyl-silylethoxymethyl)-1H-imidazol-2-yl]carbamoyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate

From trans-3-(ethylsulfamoyl)-4-[2-[4-(isopropyloxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoic acid (Compound 48) and1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine, using GeneralMethod A. ESI [M−H]=691.3.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylcarbamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 94)

From isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[1-(2-trimethyl-silylethoxymethyl)-1H-imidazol-2-yl]carbamoyl]phenyl]thiazol-2-yl]cyclohexyl]carbamate,using General Method I. ¹H NMR (400 MHz, methanol-d₄) δ=8.78 (d, J=1.63Hz, 1H), 8.28 (dd, J=8.00, 1.63 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=7.88Hz, 1H), 7.29 (s, 2H), 4.77-4.84 (m, 1H), 3.42-3.53 (m, 1H), 3.07 (tt,J=11.99, 3.39 Hz, 1H), 2.90 (q, J=7.21 Hz, 2H), 2.29 (br d, J=12.76 Hz,2H), 2.05-2.14 (m, 2H), 1.74 (qd, J=12.88, 3.00 Hz, 2H), 1.45 (qd,J=12.51, 3.00 Hz, 2H), 1.20-1.31 (m, 6H), 1.03 (t, J=7.19 Hz, 3H). ESI[M+H]=561.2.

Example 69 Preparation of isopropyltrans-N-[4-[5-[4-carbamoyl-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 49)

Fromtrans-3-(ethylsulfamoyl)-4-[2-[4-(isopropyloxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoicacid (Compound 48) and ammonium chloride, using General Method A. ¹H NMR(400 MHz, methanol-d₄) δ=8.56 (d, J=1.5 Hz, 1H), 8.09 (dd, J=1.8, 7.9Hz, 1H), 7.85 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 4.85-4.74 (m, 1H),3.52-3.40 (m, 1H), 3.05 (tt, J=3.5, 11.9 Hz, 1H), 2.89 (q, J=7.2 Hz,2H), 2.32-2.20 (m, 2H), 2.11-2.04 (m, 2H), 1.71 (dq, J=2.8, 13.0 Hz,2H), 1.48-1.36 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.02 (t, J=7.3 Hz,3H). ESI [M+H]=495.1.

Example 70 Preparation of isopropyl(trans-4-(5-(2-(N-ethylsulfamoyl)-4-(isopropylcarbamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 50)

Following the same protocol and under the same reaction conditions asfor Compound 94, Compound 50 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.52 (s, 1H), 8.05 (br d, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.61 (d, J=7.9Hz, 1H), 4.88-4.80 (m, 1H), 4.25 (quin, J=6.6 Hz, 1H), 3.48 (ddd, J=4.2,7.7, 11.4 Hz, 1H), 3.12-2.99 (m, 1H), 2.91 (q, J=7.1 Hz, 2H), 2.27 (brd, J=12.5 Hz, 2H), 2.17-2.02 (m, 2H), 1.84-1.64 (m, 2H), 1.49-1.40 (m,2H), 1.30 (d, J=6.6 Hz, 6H), 1.27-1.16 (m, 6H), 1.04 (t, J=7.2 Hz, 3H).ESI [M+H]=537.2.

Example 71 Preparation of isopropyltrans-N-[4-[5-[4-pyrrolidin-1-ylcarbonyl-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 95)

Following the same protocol and under the same reaction conditions asfor Compound 94, Compound 95 was prepared. ¹H NMR (400 MHz, methanol-d₄)δ=8.20 (d, J=1.5 Hz, 1H), 7.85-7.76 (m, 2H), 7.60 (d, J=7.9 Hz, 1H),4.84-4.76 (m, 1H), 3.63 (t, J=6.8 Hz, 2H), 3.51 (t, J=6.5 Hz, 2H),3.48-3.40 (m, 1H), 3.03 (tt, J=3.5, 12.0 Hz, 1H), 2.88 (q, J=7.3 Hz,2H), 2.30-2.19 (m, 2H), 2.07 (br dd, J=3.2, 13.3 Hz, 2H), 2.03-1.90 (m,4H), 1.71 (dq, J=2.9, 12.9 Hz, 2H), 1.47-1.36 (m, 2H), 1.22 (br d, J=6.2Hz, 6H), 1.02 (t, J=7.3 Hz, 3H). ESI [M+H]=549.3.

Example 72 Preparation of oxetan-3-yltrans-N-[4-[5-[4-carbamoyl-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 67)

Fromtrans-3-(ethylsulfamoyl)-4-[2-[4-(oxetan-3-yloxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoicacid (Compound 66) and ammonium chloride, using General Method A. ¹H NMR(400 MHz, methanol-d₄) δ=8.56 (d, J=1.8 Hz, 1H), 8.08 (dd, J=1.8, 7.9Hz, 1H), 7.81 (s, 1H), 7.60 (d, J=7.9 Hz, 1H), 5.35 (quin, J=5.7 Hz,1H), 4.84 (br s, 2H), 4.65-4.54 (m, 2H), 3.45 (ddd, J=3.7, 7.7, 11.5 Hz,1H), 3.09-2.97 (m, 1H), 2.89 (q, J=7.3 Hz, 2H), 2.29-2.19 (m, 2H), 2.08(br d, J=10.4 Hz, 2H), 1.71 (dq, J=3.0, 12.8 Hz, 2H), 1.50-1.36 (m, 2H),1.02 (t, J=7.2 Hz, 3H). ESI [M+H]=509.2.

Example 73 Preparation of oxetan-3-yl(trans-4-(5-(2-(N-ethylsulfamoyl)-4-(isopropylcarbamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 68)

Following the same protocol and under the same reaction conditions asfor Compound 67, Compound 68 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=8.53 (d, J=7.7 Hz, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.07 (dd, J=1.7, 8.0Hz, 1H), 7.76 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.53 (br s, 1H), 7.43 (d,J=7.5 Hz, 1H), 5.26 (quin, J=5.7 Hz, 1H), 4.73 (t, J=6.9 Hz, 2H),4.46-4.40 (m, 2H), 4.15-4.03 (m, 1H), 3.29 (s, 1H), 2.94 (tt, J=3.6,11.9 Hz, 1H), 2.77 (q, J=7.1 Hz, 2H), 2.14 (br d, J=11.7 Hz, 2H), 1.91(br d, J=9.7 Hz, 2H), 1.62-1.51 (m, 2H), 1.41-1.30 (m, 2H), 1.16 (d,J=6.6 Hz, 6H), 0.93 (t, J=7.3 Hz, 3H). ESI [M+H]=551.2.

Example 74 Preparation of isopropyltrans-N-[4-[5-[4-[2-(benzylamino)-2-oxo-ethyl]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 97)

a) Synthesis of methyl 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetate

To a solution of 2-methylpropan-2-amine (2.6 g, 36.6 mmol, 3 eq.) in DCM(60 mL) was added DMAP (149 mg, 1 mmol, 0.1 eq.), and methyl2-(4-bromo-3-chlorosulfonyl-phenyl)acetate (4.0 g, 12.2 mmol, 1 eq.) at0° C. The mixture was stirred at 25° C. for 2 h, then diluted with H₂O(100 mL) and extracted with DCM 400 mL (200 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was slurried in the solution (petroleumether:ethyl acetate=20:1, 10 mL) for 1 h. Then it was filtered to yieldmethyl 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetate (2.2 g, 6.0mmol, 49.4% yield) as a yellow solid. ¹H NMR (400 MHz, methanol-d₄)δ=8.16-8.00 (m, 1H), 7.80-7.62 (m, 1H), 7.36 (dd, J=2.0, 8.2 Hz, 1H),3.73 (s, 2H), 3.69-3.64 (m, 3H), 1.21-1.15 (m, 9H).ESI[M−H]=361.9/363.9.

b) Synthesis of 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetic acid

From methyl 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetate, usingGeneral Method J.

c) Synthesis ofN-benzyl-2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetamide

From 2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetic acid andbenzylamine, using General Method A. ¹H NMR (400 MHz, methanol-d₄)δ=8.11 (d, J=2.0 Hz, 1H), 7.76-7.65 (m, 1H), 7.44-7.33 (m, 2H),7.32-7.18 (m, 4H), 4.36 (s, 2H), 3.59 (s, 2H), 1.21-1.10 (m, 9H). ESI[M+H]=439.0/441.0.

d) Synthesis ofN-benzyl-2-[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

From N-benzyl-2-[4-bromo-3-(tert-butylsulfamoyl)phenyl]acetamide, usingGeneral Method B. ESI[M+H]=487.2.

e) Synthesis of isopropyltrans-N-[4-[5-[4-[2-(benzylamino)-2-oxo-ethyl]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 97)

FromN-benzyl-2-[3-(tert-butylsulfamoyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide,using General Method C. ¹H NMR (400 MHz, methanol-d₄) δ=8.14 (d, J=1.5Hz, 1H), 7.79 (s, 1H), 7.56 (dd, J=1.7, 7.8 Hz, 1H), 7.43 (d, J=7.7 Hz,1H), 7.34-7.19 (m, 5H), 4.84 (br s, 1H), 4.38 (s, 2H), 3.67 (s, 2H),3.51-3.39 (m, 1H), 3.03 (tt, J=3.4, 12.0 Hz, 1H), 2.23 (br d, J=12.6 Hz,2H), 2.07 (br d, J=10.6 Hz, 2H), 1.76-1.60 (m, 2H), 1.41 (dq, J=3.2,12.5 Hz, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.13-0.99 (m, 9H). ESI[M+H]=627.3.

Example 75 Preparation of oxetan-3-yltrans-N-[4-[5-[4-[2-(benzylamino)-2-oxo-ethyl]-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 98)

Following the same protocol and under the same reaction conditions asfor Compound 97, Compound 98 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=8.66 (t, J=6.0 Hz, 1H), 8.01 (s, 1H), 7.68 (s, 1H), 7.50 (br d, J=7.9Hz, 1H), 7.45-7.36 (m, 2H), 7.33-7.26 (m, 2H), 7.25-7.18 (m, 3H), 6.94(s, 1H), 5.26 (quin, J=5.7 Hz, 1H), 4.73 (t, J=6.9 Hz, 2H), 4.52-4.39(m, 2H), 4.26 (d, J=5.7 Hz, 2H), 3.60 (s, 2H), 3.30-3.20 (m, 1H),2.99-2.82 (m, 1H), 2.12 (br d, J=11.5 Hz, 2H), 1.90 (br d, J=10.4 Hz,2H), 1.65-1.48 (m, 2H), 1.42-1.27 (m, 2H), 1.00 (s, 9H). ESI[M+H]=641.3.

Example 76 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 99)

a) Synthesis of 2-bromo-N-ethyl-5-hydroxy-benzenesulfonamide

To a solution of 5-amino-2-bromo-N-ethyl-benzenesulfonamide (5 g, 17.91mmol, 1 eq) in H₂O (200 mL) was added trifluoroborane; hydrofluoride(7.8 g, 35.8 mmol, 200 mL, 40% purity). Then NaNO₂ (1.4 g, 19.7 mmol,1.1 eq) in H₂O (140 mL) was added batch at 0° C. for 30 mins. Then,sat.aq. CuSO₄ (416.0 g, 2.6 mol, 145.52 eq) and CuO (1.42 g, 17.91 mmol,225.44 uL, 1 eq) was added batchwise. The mixture was stirred at 20° C.for 2 h. The reaction mixture was extracted with DCM 150 mL (50 mL×3).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified byreversed-phase HPLC (0.1% TFA condition) to yield2-bromo-N-ethyl-5-hydroxy-benzenesulfonamide (2.2 g) as a yellow gum.ESI [M+H]=279.9/281.9.

b) Synthesis of 2-bromo-N-ethyl-5-isopentyloxy-benzenesulfonamide

A mixture of 2-bromo-N-ethyl-5-hydroxy-benzenesulfonamide (700 mg, 2.5mmol, 1 eq), 1-bromo-3-methyl-butane (1.1 g, 7.5 mol, 3.0 eq), K₂CO₃(1.0 g, 7.5 mmol, 3.0 eq) in DMF (7 mL) was stirred at 60° C. for 2 hunder N₂ atmosphere. The reaction mixture was quenched by H₂O 70 mL andextracted with EtOAc 120 mL (40 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=50:1 to 0:1) to yield2-bromo-N-ethyl-5-isopentyloxy-benzenesulfonamide (920 mg) as colorlessoil. ¹H NMR (400 MHz, methanol-d₄) δ=7.65 (d, J=8.8 Hz, 1H), 7.59 (d,J=2.9 Hz, 1H), 7.16-7.15 (m, 1H), 4.06 (t, J=6.5 Hz, 2H), 2.94 (q, J=7.2Hz, 2H), 1.84 (td, J=6.7, 13.5 Hz, 1H), 1.74-1.61 (m, 2H), 1.06 (t,J=7.2 Hz, 3H), 0.98 (d, J=6.6 Hz, 6H). ESI [M+H]=349.9/352.0.

c) Synthesis ofN-ethyl-5-isopentyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)benzenesulfonamide

From 2-bromo-N-ethyl-5-isopentyloxy-benzenesulfonamide, using GeneralMethod B. ¹H NMR (400 MHz, methanol-d₄) δ=7.64 (d, J=8.2 Hz, 1H), 7.42(d, J=2.4 Hz, 1H), 7.14 (dd, J=2.5, 8.3 Hz, 1H), 4.09 (t, J=6.5 Hz, 2H),2.90 (q, J=7.3 Hz, 2H), 1.70 (q, J=6.6 Hz, 2H), 1.39 (s, 1H), 1.38 (s,12H), 1.03 (t, J=7.2 Hz, 3H), 0.98 (d, J=6.6 Hz, 6H). ESI [M+H]=398.1.

d) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 99)

FromN-ethyl-5-isopentyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide, using General Method C. ¹H NMR (400 MHz, DMSO-d₆) δ=7.60(s, 1H), 7.46 (t, J=5.6 Hz, 1H), 7.43-7.36 (m, 2H), 7.19 (dd, J=2.6, 8.6Hz, 1H), 7.01 (br d, J=7.7 Hz, 1H), 4.72 (td, J=6.3, 12.4 Hz, 1H), 4.08(t, J=6.5 Hz, 2H), 3.36-3.22 (m, 1H), 2.93-2.84 (m, 1H), 2.82-2.72 (m,2H), 2.11 (br d, J=11.9 Hz, 2H), 1.89 (br d, J=10.4 Hz, 2H), 1.82-1.71(m, 1H), 1.63 (q, J=6.5 Hz, 2H), 1.54 (dq, J=2.8, 12.8 Hz, 2H),1.38-1.25 (m, 2H), 1.14 (d, J=6.2 Hz, 6H), 0.98-0.93 (m, 3H), 0.92 (d,J=6.6 Hz, 6H). ESI [M+H]=538.2.

Example 77 Preparation of oxetan-3-yltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 100)

Following the same protocol and under the same reaction conditions asfor Compound 99, Compound 100 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=7.60 (s, 1H), 7.55-7.29 (m, 4H), 7.19 (dd, J=2.5, 8.5 Hz, 1H), 5.25(quin, J=5.7 Hz, 1H), 4.73 (t, J=6.8 Hz, 2H), 4.49-4.37 (m, 2H), 4.08(t, J=6.5 Hz, 2H), 3.30-3.25 (m, 1H), 2.90 (tt, J=3.3, 11.8 Hz, 1H),2.78 (q, J=7.3 Hz, 2H), 2.12 (br d, J=11.9 Hz, 2H), 1.90 (br d, J=10.6Hz, 2H), 1.83-1.70 (m, 1H), 1.67-1.59 (m, 2H), 1.59-1.46 (m, 2H),1.39-1.29 (m, 2H), 0.98-0.93 (m, 3H), 0.92 (d, J=6.4 Hz, 6H). ESI[M+H]=552.2.

Example 78 Preparation of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 101)

a) Synthesis of 2-bromo-N-tert-butyl-5-hydroxy-benzenesulfonamide

To isopropyl 5-amino-2-bromo-N-tert-butyl-benzenesulfonamide (10.0 g,32.6 mmol, 1.0 eq.) dissolved in H₂SO₄ (120 mL, 30% aq.) was added asolution of NaNO₂ (2.3 g, 1.1 mol, 34.5 eq.) in H₂O (20 mL) at 0° C. andthe mixture was stirred at 0° C. for 30 min. Then was added H₂O (280 mL)to the mixture and stirred at 65° C. for 11 h. The mixture was extractedwith EtOAc (300 mL×3). The combined organic layers were dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by reversed-phase chromatography to yield2-bromo-N-tert-butyl-5-hydroxy-benzene sulfonamide (1.4 g, 4.5 mmol, 14%yield) was obtained as a red solid. ESI [M−H]=305.8/307.8.

b) Synthesis of 2-bromo-N-tert-butyl-5-isopentyloxy-benzenesulfonamide

To a solution of 2-bromo-N-tert-butyl-5-hydroxy-benzenesulfonamide (1.5g, 4.7 mmol, 1.0 eq.) in DMF (30 mL) was added K₂CO₃ (2.0 g, 14.1 mmol,3.0 eq.) and 1-bromo-3-methyl-butane (1.1 g, 7.1 mmol, 1.5 eq.). Thereaction mixture was stirred at 100° C. for 12 h. The mixture was pouredinto water (100 mL) and the solid filtrated, yielding2-bromo-N-tert-butyl-5-isopentyloxy-benzenesulfonamide (1.4 g, crude) asa yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.61-7.70 (m, 2H), 7.04(dd, J=8.68, 2.69 Hz, 1H), 4.08 (t, J=6.54 Hz, 2H), 1.80-1.92 (m, 1H),1.71 (q, J=6.48 Hz, 2H), 1.14-1.26 (m, 9H), 0.99 (s, 6H).

c) Synthesis ofN-tert-butyl-5-isopentyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide

From 2-bromo-N-tert-butyl-5-isopentyloxy-benzenesulfonamide, usingGeneral Method B. ¹H NMR (400 MHz, CDCl₃) δ=7.66 (d, J=8.2 Hz, 1H), 7.50(d, J=2.4 Hz, 1H), 6.92-6.89 (m, 1H), 3.98-3.94 (m, 2H), 1.64-1.59 (m,3H), 1.32 (s, 12H), 1.14 (s, 9H), 0.91-0.88 (m, 6H). ESI [M+H]=426.2.

d) Synthesis of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 101)

FromN-tert-butyl-5-isopentyloxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide,using General Method C. ¹H NMR (400 MHz, methanol-d₄) δ=7.68-7.53 (m,2H), 7.30 (d, J=8.4 Hz, 1H), 7.08 (dd, J=2.6, 8.4 Hz, 1H), 4.77-4.69 (m,1H), 4.03 (t, J=6.5 Hz, 2H), 3.36 (ddd, J=3.9, 7.8, 11.5 Hz, 1H), 2.92(br t, J=12.1 Hz, 1H), 2.14 (br d, J=12.2 Hz, 2H), 1.98 (br d, J=10.6Hz, 2H), 1.83-1.71 (m, 1H), 1.67-1.54 (m, 4H), 1.38-1.24 (m, 2H), 1.14(br d, J=6.1 Hz, 6H), 1.01 (s, 9H), 0.91 (d, J=6.6 Hz, 6H). ESI[M+H]=566.2.

Example 79 Preparation of oxetan-3-yltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-isopentyloxy-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 102)

Following the same protocol and under the same reaction conditions asfor Compound 101, Compound 102 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.73-7.65 (m, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.18 (dd,J=2.6, 8.5 Hz, 1H), 5.45-5.32 (m, 1H), 4.87 (br s, 2H), 4.66-4.59 (m,2H), 4.14 (t, J=6.5 Hz, 2H), 3.52-3.40 (m, 1H), 3.03 (br t, J=12.0 Hz,1H), 2.25 (br d, J=12.3 Hz, 2H), 2.09 (br d, J=11.6 Hz, 2H), 1.89(quind, J=6.7, 13.4 Hz, 1H), 1.79-1.64 (m, 4H), 1.52-1.39 (m, 2H), 1.11(s, 9H), 1.02 (d, J=6.6 Hz, 6H). ESI [M+H]=580.2.

Example 80 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(oxazol-2-ylmethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 103)

a) Synthesis oftrans-2-[2-(4-aminocyclohexyl)thiazol-5-yl]-N-ethyl-5-(oxazol-2-ylmethyl)benzenesulfonamide

A mixture of isopropyltrans-N-[4-[5-[4-[2-(2,2-dimethoxyethylamino)-2-oxo-ethyl]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(50 mg, 83 umol, 1 eq.) in PPA (1 mL) was stirred at 70° C. for 1 h thenthe mixture warmed to 120° C. for 3 h. The reaction mixture was dilutedwith MeOH (1 mL). The residue was purified by prep-HPLC (column:Phenomenex Luna C18 100*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN];B %: 10%-35%,12 min) to yieldtrans-2-[2-(4-amino-cyclohexyl)thiazol-5-yl]-N-ethyl-5-(oxazol-2-ylmethyl)benzenesulfonamide(5 mg, 9 umol, 11% yield, TFA) as a white solid. ESI [M+H]=447.2.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(oxazol-2-yl-methyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 103)

To a solution oftrans-2-[2-(4-aminocyclohexyl)thiazol-5-yl]-N-ethyl-5-(oxazol-2-ylmethyl)benzenesulfonamide(5 mg, 9 umol, 1 eq., TFA) in dioxane (1 mL) was added sat.aq. Na₂CO₃(0.3 mL) and isopropyl chloroformate (2 mg, 17 umol, 2 eq.). The mixturewas stirred at 25° C. for 2 h. The reaction mixture was concentratedunder reduced pressure and purified by prep-HPLC (column: Welch UltimateAQ-C18 150*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN]; B %:33%-63%,12 min) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(oxazol-2-ylmethyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(720 ug, 1 umol, 14% yield, 95% purity) as a yellow gum. ¹H NMR (400MHz, methanol-d₄) δ=7.89 (d, J=1.3 Hz, 1H), 7.78 (s, 1H), 7.63 (s, 1H),7.48 (dd, J=1.4, 7.9 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.04 (s, 1H), 4.54(br s, 1H), 4.21 (s, 2H), 3.40-3.34 (m, 1H), 2.97-2.87 (m, 1H), 2.75 (q,J=7.3 Hz, 2H), 2.18-2.08 (m, 2H), 2.02-1.92 (m, 2H), 1.66-1.55 (m, 2H),1.38-1.28 (m, 2H), 1.13 (br d, J=6.1 Hz, 6H), 0.91 (t, J=7.3 Hz, 3H).ESI [M+H]=533.0.

Example 81 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-oxazol-2-yl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 104)

a) Synthesis of isopropyltrans-N-[4-[5-[4-(2,2-dimethoxyethylcarbamoyl)-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

Fromtrans-3-(ethylsulfamoyl)-4-[2-[4-(isopropyloxycarbonyl-amino)cyclohexyl]thiazol-5-yl]benzoicacid (Compound 48), using General Method A. ¹H NMR (400 MHz,methanol-d₄) δ=8.54 (s, 1H), 8.06 (br d, J=7.9 Hz, 1H), 7.84 (s, 1H),7.63 (br d, J=7.8 Hz, 1H), 5.00-4.96 (m, 1H), 4.61 (br t, J=5.5 Hz, 1H),3.55 (br d, J=5.3 Hz, 2H), 3.49 (br d, J=11.0 Hz, 1H), 3.44 (s, 6H),3.37 (br d, J=5.3 Hz, 1H), 2.95-2.89 (m, 2H), 2.35-2.23 (m, 2H), 2.10(br d, J=10.8 Hz, 2H), 1.79-1.67 (m, 2H), 1.53-1.43 (m, 2H), 1.25 (br d,J=5.9 Hz, 6H), 1.10-0.98 (m, 3H). ESI [M+H]=583.2.

b) Synthesis oftrans-2-[2-(4-aminocyclohexyl)thiazol-5-yl]-N-ethyl-5-oxazol-2-yl-benzenesulfonamide

A solution of isopropyltrans-N-[4-[5-[4-(2,2-dimethoxyethylcarbamoyl)-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(50 mg, 85 umol, 1 eq.) in PPA (2 mL) was stirred at 70° C. for 1 h thenwarmed to 120° C. stirred for 2 h. The reaction was concentrated underreduced pressure. The residue was purified by prep-HPLC (column:Nano-micro Kromasil C18 80*25 mm 3 um; mobile phase: [water(0.1%TFA)-ACN]; B %: 15%-45%,7 min) to yieldtrans-2-[2-(4-aminocyclohexyl)thiazol-5-yl]-N-ethyl-5-oxazol-2-yl-benzenesulfonamide(17 mg, 31 umol, 36% yield, TFA) as brown oil. ESI [M+H]=433.2.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-oxazol-2-yl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 104)

To a solution oftrans-2-[2-(4-aminocyclohexyl)thiazol-5-yl]-N-ethyl-5-oxazol-2-yl-benzenesulfonamide(15 mg, 27 umol, 1 eq., TFA) in dioxane (2 mL) was added sat.aq. Na₂CO₃(0.3 mL) and isopropyl chloroformate (26 mg, 213 umol, 8 eq.). Themixture was stirred at 25° C. for 1 h. The reaction was concentrated andpurified by prep-HPLC (column: Nano-micro Kromasil C18 80*25 mm 3 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 45%-62%,7 min) to yieldisopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-oxazol-2-yl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(2 mg, 4 umol, 11% yield, 94% purity) as a yellow solid. ¹H NMR (400MHz, methanol-d₄) δ=8.72 (d, J=1.5 Hz, 1H), 8.27 (dd, J=1.8, 8.0 Hz,1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.41 (s, 1H),4.96-4.91 (m, 1H), 3.53-3.43 (m, 1H), 3.10-3.02 (m, 1H), 2.95 (q, J=7.3Hz, 2H), 2.28 (br d, J=12.1 Hz, 2H), 2.14-2.04 (m, 2H), 1.80-1.67 (m,2H), 1.44 (dq, J=2.9, 12.6 Hz, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.07 (t,J=7.2 Hz, 3H). ESI [M+H]=519.0.

Example 82 Preparation of compound isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-methylimidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 105) and isopropylcis-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-methylimidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 106)

From isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 2-bromo-1-methyl-1H-imidazole, using General Method K. (Compound105), ¹H NMR (400 MHz, methanol-d₄) δ=7.74 (d, J=2.4 Hz, 1H), 7.63-7.54(m, 1H), 7.40-7.23 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.92 (d, J=1.8 Hz,1H), 4.72 (br d, J=6.2 Hz, 1H), 3.61-3.51 (m, 3H), 3.42-3.30 (m, 1H),2.96-2.87 (m, 1H), 2.77 (q, J=7.2 Hz, 2H), 2.18-2.09 (m, 2H), 1.97 (brd, J=9.9 Hz, 2H), 1.59 (dq, J=2.9, 12.9 Hz, 2H), 1.37-1.24 (m, 2H), 1.13(br d, J=6.1 Hz, 6H), 0.91 (t, J=7.2 Hz, 3H). ESI [M+H]=547.2. (Compound106), ¹ H NMR (400 MHz, methanol-d₄) δ=7.73 (d, J=2.3 Hz, 1H), 7.69 (s,1H), 7.37-7.31 (m, 1H), 7.25 (dd, J=2.4, 8.4 Hz, 1H), 6.97 (d, J=1.2 Hz,1H), 6.86 (d, J=1.3 Hz, 1H), 4.84 (br s, 1H), 3.77 (br d, J=4.9 Hz, 1H),3.60 (s, 3H), 3.17 (br dd, J=4.2, 8.6 Hz, 1H), 2.91 (q, J=7.2 Hz, 2H),2.09-1.94 (m, 4H), 1.91-1.71 (m, 4H), 1.25 (d, J=6.2 Hz, 6H), 1.05 (t,J=7.2 Hz, 3H). ESI [M+H]=547.2.

Example 83 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isobutylimidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 107)

a) Synthesis of 2-bromo-1-isobutyl-1H-imidazole

To a mixture of 2-bromo-1H-imidazole (300 mg, 2 mmol, 1 eq.), NaH (245mg, 6 mmol, 60% purity, 3 eq.) in THF (3 mL) was added1-bromo-2-methyl-propane (838.55 mg, 6.12 mmol, 665.52 uL, 3 eq.) andstirred at 25° C. for 6 h under N₂ atmosphere. The reaction mixture wasquenched by addition H₂O 10 mL, extracted with EtOAc 60 mL (20 mL×3).The combined organic layers were washed with sat.aq. NaCl 60 mL (12mL×5), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (Nano-micro Kromasil C18100*30 mm 5 um; mobile phase: [water(0.1% TFA)-ACN]; B %:3%-35%,7 min)to yield 2-bromo-1-isobutyl-1H-imidazole (400 mg, 2 mmol, 97% yield) asyellow oil. ¹H NMR (400 MHz, CDCl₃) δ=7.37 (d, J=1.76 Hz, 1H), 7.10 (d,J=1.76 Hz, 1H), 3.84 (d, J=7.50 Hz, 2H), 2.05-2.27 (m, 1H), 0.98 (d,J=6.84 Hz, 6H). ESI [M+H]=203.0/205.0.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isobutyl-imidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 107)

From isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 2-bromo-1-isobutyl-1H-imidazole, using General Method K. ¹H NMR (400MHz, methanol-d₄) δ=7.63-7.70 (m, 2H), 7.31 (d, J=8.38 Hz, 1H), 7.18(dd, J=2.43, 8.38 Hz, 1H), 7.00 (d, J=1.54 Hz, 1H), 6.88 (d, J=1.54 Hz,1H), 4.83 (br d, J=6.39 Hz, 1H), 3.69-3.79 (m, 2H), 3.45 (br t, J=11.80Hz, 1H), 2.93-3.05 (m, 1H), 2.86 (q, J=7.28 Hz, 2H), 2.23 (br d, J=12.79Hz, 2H), 2.01-2.12 (m, 3H), 1.63-1.75 (m, 2H), 1.35-1.47 (m, 2H), 1.23(br d, J=6.17 Hz, 6H), 1.01 (t, J=7.28 Hz, 3H), 0.90 (d, J=6.62 Hz, 6H).ESI [M+H]=589.3.

Example 84 Preparation of cyclopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 109)

a) Synthesis of cyclopropyltrans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate

To a solution of cyclopropanol (293 mg, 5 mmol, 5 eq) in DCE (3 mL) wasadded DIEA (651 mg, 5 mmol, 5 eq) at 0° C. The mixture was stirred at 0°C. for 10 min, followed by the addition of triphosgene (598 mg, 2 mmol,2 eq) at 0° C. The mixture was stirred at 25° C. for 30 min (mixture 1).To a solution of trans-4-(5-bromothiazol-2-yl)cyclohexanamine (300 mg, 1mmol, 1 eq, HCl) in DIEA (3 mL) was added mixture 1 and stirred at 25°C. for 2 h. The reaction mixture was quenched by addition sat.aq. Na₂CO₃5 mL, and extracted with dichloromethane 30 mL (10 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified prep-TLC (SiO₂, petroleumether:ethyl acetate=2:1) to yield cyclopropyltrans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamate (140 mg, 406 umol,40% yield) as a yellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.60 (s,1H), 3.95 (br d, J=3.3 Hz, 1H), 3.43 (br s, 1H), 3.04-2.81 (m, 1H),2.22-1.89 (m, 4H), 1.72-1.49 (m, 2H), 1.46-1.11 (m, 4H), 0.65-0.61 (m,2H). ESI [M+H]=345.1/347.0.

b) Synthesis of cyclopropyl trans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (Compound 108)

From cyclopropyl trans-N-[4-(5-bromothiazol-2-yl)cyclohexyl]carbamateand5-amino-N-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide,using General Method C. ¹H NMR (400 MHz, methanol-d₄) δ=7.74 (s, 1H),7.40 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 6.91 (dd, J=2.4, 8.4 Hz,1H), 3.96 (br d, J=3.3 Hz, 1H), 3.47 (br t, J=11.5 Hz, 1H), 3.06 (br t,J=12.2 Hz, 1H), 2.87 (q, J=7.3 Hz, 2H), 2.23 (br d, J=12.8 Hz, 2H),2.13-1.95 (m, 2H), 1.83-1.59 (m, 2H), 1.41 (dq, J=3.2, 12.6 Hz, 2H),1.02 (t, J=7.2 Hz, 3H), 0.63 (br d, J=5.1 Hz, 4H). ESI [M+H]=465.1.

c) Synthesis of cyclopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 109)

From cyclopropyl trans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (Compound 108) and2-bromo-1H-imidazole, using General Method K. ¹H NMR (400 MHz,methanol-d₄) δ=7.90 (d, J=1.5 Hz, 1H), 7.72 (s, 1H), 7.53-7.40 (m, 2H),7.05 (s, 2H), 3.97 (br d, J=3.5 Hz, 1H), 3.47 (br s, 1H), 3.01 (br t,J=11.9 Hz, 1H), 2.87 (q, J=7.3 Hz, 2H), 2.25 (br d, J=12.8 Hz, 2H), 2.08(br d, J=10.1 Hz, 2H), 1.85-1.63 (m, 2H), 1.50-1.33 (m, 2H), 1.01 (t,J=7.2 Hz, 3H), 0.64 (br d, J=4.6 Hz, 4H). ESI [M+H]=531.1.

Example 85 Preparation of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 38) and isopropylcis-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 110)

From isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 2-bromo-1H-imidazole, using General Method K. (Compound 38), ¹H NMR(400 MHz, methanol-d₄) δ=7.95 (t, J=1.3 Hz, 1H), 7.73 (s, 1H), 7.47 (d,J=1.3 Hz, 2H), 7.04 (s, 2H), 4.85-4.79 (m, 1H), 3.55-3.37 (m, 1H), 3.01(tt, J=3.5, 12.0 Hz, 1H), 2.32-2.16 (m, 2H), 2.13-1.99 (m, 2H), 1.69(dq, J=3.1, 12.9 Hz, 2H), 1.41 (dq, J=3.2, 12.5 Hz, 2H), 1.22 (br d,J=6.2 Hz, 6H), 1.09 (s, 9H). ESI [M+H]=561.2. (Compound 110), ¹H NMR(400 MHz, methanol-d₄) δ=7.96 (d, J=2.2 Hz, 1H), 7.76 (s, 1H), 7.59-7.42(m, 2H), 7.08 (s, 2H), 4.83-4.75 (m, 1H), 3.82-3.66 (m, 1H), 3.23-3.08(m, 1H), 2.08-1.92 (m, 4H), 1.89-1.68 (m, 4H), 1.23 (d, J=6.2 Hz, 6H),1.10 (s, 9H). ESI [M+H]=561.2.

Example 86 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(4-isopropyl-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 111)

a) Synthesis of 4-isopropenylpyridin-2-amine

A mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.53g, 15 mmol, 1.3 eq.), 4-bromopyridin-2-amine (2 g, 12 mmol, 1.0 eq.),Cs₂CO₃ (11.3 g, 35 mmol, 3.0 eq.) and Pd(dppf)Cl₂ (846 mg, 1 mmol, 0.1eq.) in H₂O (50 mL) and dioxane (100 mL) was stirred at 90° C. for 4 hunder N₂ atmosphere. The reaction was concentrated, and then purified bycolumn chromatography (SiO₂, petroleum ether:ethyl acetate=10:1 to 1:1)to yield 4-isopropenylpyridin-2-amine (1.5 g, 11 mmol, 97% yield) as abrown solid. ESI [M+H]=135.1.

b) Synthesis of 4-isopropylpyridin-2-amine

A mixture of 4-isopropenylpyridin-2-amine (1.5 g, 11 mmol, 1 eq.), Pd/C(500 mg, 10% purity) in EtOAc (300 mL) was degassed and purged with H₂(30 psi) for 3 times, and then the mixture was stirred at 25° C. for 12h under H₂ atmosphere. The reaction mixture was filtered, and thefiltrate was concentrated. The residue was purified by prep-HPLC(Neutral condition: column: Waters Xbridge Prep OBD C18 150*40 mm*10 um;mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %: 15%-45%,8 min) to yield4-isopropylpyridin-2-amine (800 mg, 6 mmol, 53% yield) as yellow oil. ¹HNMR (400 MHz, methanol-d₄) δ=7.78 (d, J=5.5 Hz, 1H), 6.56-6.44 (m, 2H),2.82-2.71 (m, 1H), 1.23 (d, J=6.9 Hz, 6H). ESI [M+H]=137.0.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(4-isopropyl-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 111)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 4-isopropylpyridin-2-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.16 (d, J=2.3 Hz, 1H), 7.97 (d, J=6.9 Hz, 1H), 7.79 (s,1H), 7.72 (dd, J=2.2, 8.3 Hz, 1H), 7.60 (d, J=8.1 Hz, 1H), 7.11-7.08 (m,2H), 4.85-4.85 (m, 1H), 3.48 (br t, J=11.5 Hz, 1H), 3.10-2.98 (m, 2H),2.91 (q, J=7.2 Hz, 2H), 2.28 (br d, J=12.6 Hz, 2H), 2.10 (br d, J=10.8Hz, 2H), 1.80-1.67 (m, 2H), 1.51-1.38 (m, 2H), 1.33 (d, J=6.9 Hz, 6H),1.25 (br d, J=6.1 Hz, 6H), 1.05 (t, J=7.3 Hz, 3H). ESI [M+H]=586.3.

Example 87 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropyl-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 112)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 112 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.46 (d, J=2.0 Hz, 1H), 7.85-7.77 (m, 2H), 7.76 (s, 1H),7.48 (d, J=8.3 Hz, 1H), 6.91 (d, J=7.9 Hz, 2H), 4.82 (br s, 1H),3.54-3.43 (m, 1H), 3.13-3.00 (m, 2H), 2.91 (q, J=7.2 Hz, 2H), 2.32-2.23(m, 2H), 2.10 (br dd, J=2.9, 12.8 Hz, 2H), 1.80-1.67 (m, 2H), 1.50-1.41(m, 2H), 1.38 (d, J=7.0 Hz, 6H), 1.25 (br d, J=6.1 Hz, 6H), 1.04 (t,J=7.2 Hz, 3H). ESI [M+H]=586.1.

Example 88 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropyl-2-pyridyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 113)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 113 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.05-7.99 (m, 1H), 7.96-7.89 (m, 1H), 7.79 (s, 1H), 7.67(s, 1H), 7.62-7.55 (m, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.21-7.07 (m, 1H),4.74-4.70 (m, 1H), 3.36 (tt, J=3.9, 11.6 Hz, 1H), 2.98-2.84 (m, 2H),2.80 (q, J=7.2 Hz, 2H), 2.16 (br d, J=12.1 Hz, 2H), 1.98 (br d, J=10.3Hz, 2H), 1.61 (dq, J=2.3, 12.7 Hz, 2H), 1.38-1.25 (m, 2H), 1.20 (d,J=7.0 Hz, 6H), 1.13 (br d, J=6.2 Hz, 6H), 0.93 (t, J=7.2 Hz, 3H). ESI[M+H]=586.1.

Example 89 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[3-isopropoxyazetidin-1-yl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 114)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 114 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.62 (s, 1H), 7.28 (d, J=8.38 Hz, 1H), 7.08 (d, J=2.38Hz, 1H), 6.68 (dd, J=8.32, 2.44 Hz, 1H), 4.72-4.80 (m, 1H), 4.57-4.63(m, 1H), 4.25 (t, J=7.25 Hz, 2H), 3.71-3.79 (m, 3H), 3.40-3.50 (m, 1H),2.93-3.05 (m, 1H), 2.87 (q, J=7.21 Hz, 2H), 2.19-2.30 (m, 2H), 2.02-2.14(m, 2H), 1.62-1.78 (m, 2H), 1.37-1.48 (m, 2H), 1.24 (br d, J=6.13 Hz,6H), 1.20 (d, J=6.13 Hz, 6H), 1.03 (t, J=7.25 Hz, 3H). ESI [M+H]=565.3.

Example 90 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropyl-1,3,4-thiadiazol-2-y)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 115)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 115 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.46 (d, J=2.25 Hz, 1H), 7.85 (dd, J=8.38, 2.38 Hz, 1H),7.77 (br s, 1H), 7.47 (d, J=8.38 Hz, 1H), 4.84 (br s, 1H), 3.42-3.53 (m,1H), 3.35-3.41 (m, 1H), 3.04 (br s, 1H), 2.97 (q, J=7.25 Hz, 2H), 2.26(br d, J=12.63 Hz, 2H), 2.09 (br d, J=10.51 Hz, 2H), 1.72 (q, J=11.30Hz, 2H), 1.43 (d, J=6.88 Hz, 8H), 1.25 (br d, J=6.00 Hz, 6H), 1.09 (t,J=7.25 Hz, 3H). ESI [M+H]=593.0.

Example 91 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-methyloxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 116)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 116 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=7.56 (s, 1H), 7.31 (br s, 1H), 7.23-7.15 (m, 1H), 7.02 (br d, J=7.7Hz, 1H), 6.98-6.90 (m, 2H), 6.52 (dd, J=2.2, 8.3 Hz, 1H), 4.80-4.70 (m,1H), 4.63 (br d, J=5.9 Hz, 2H), 4.51 (br d, J=5.7 Hz, 2H), 3.31-3.25 (m,1H), 2.93-2.82 (m, 1H), 2.81-2.77 (m, 2H), 2.18-2.07 (m, 2H), 1.91 (brd, J=10.6 Hz, 2H), 1.58 (s, 3H), 1.57-1.47 (m, 2H), 1.40-1.26 (m, 2H),1.17 (br d, J=6.1 Hz, 6H), 0.98 (t, J=7.2 Hz, 3H). ESI [M+H]=537.2.

Example 92 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[methyl(1-methyl-1H-imidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 117)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 117 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.78-7.67 (m, 1H), 7.61-7.48 (m, 4H), 7.28-7.13 (m, 1H),4.86-4.79 (m, 1H), 3.61 (s, 3H), 3.58-3.55 (m, 3H), 3.52-3.40 (m, 1H),3.08-3.00 (m, 1H), 2.85 (q, J=7.2 Hz, 2H), 2.30-2.22 (m, 2H), 2.14-2.06(m, 2H), 1.78-1.65 (m, 2H), 1.43 (dq, J=3.2, 12.7 Hz, 2H), 1.25 (br d,J=6.1 Hz, 6H), 1.04-0.99 (m, 3H). ESI [M+H]=561.3.

Example 93 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1,3,4-oxadiazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 118)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 118 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.49 (d, J=2.38 Hz, 1H), 8.31 (s, 1H), 7.93 (dd, J=8.38,2.38 Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=8.25 Hz, 1H), 4.79-4.84 (m, 1H),3.42-3.53 (m, 1H), 3.06 (tt, J=12.04, 3.35 Hz, 1H), 2.96 (q, J=7.21 Hz,2H), 2.20-2.32 (m, 2H), 2.04-2.14 (m, 2H), 1.65-1.80 (m, 2H), 1.34-1.51(m, 2H), 1.25 (br d, J=6.13 Hz, 6H), 1.02-1.12 (m, 3H). ESI [M+H]=535.2.

Example 94 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1,3,4-thiadiazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 119)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 119 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.90 (s, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.91 (dd, J=2.4,8.4 Hz, 1H), 7.79 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.84 (br s, 1H), 3.48(tt, J=3.8, 11.6 Hz, 1H), 3.12-3.03 (m, 1H), 2.99 (q, J=7.2 Hz, 2H),2.32-2.22 (m, 2H), 2.14-2.05 (m, 2H), 1.73 (dq, J=3.0, 12.9 Hz, 2H),1.44 (dq, J=3.1, 12.6 Hz, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.10 (t, J=7.2Hz, 3H). ESI [M+H]=551.2.

Example 95 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-pyrazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 120)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 120 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.68 (s, 1H), 7.61 (s, 2H), 7.45 (d, J=2.4 Hz, 1H), 7.24(d, J=8.4 Hz, 1H), 6.97 (dd, J=2.4, 8.4 Hz, 1H), 4.84-4.75 (m, 1H),3.51-3.39 (m, 1H), 3.01 (tt, J=3.4, 12.1 Hz, 1H), 2.86 (q, J=7.2 Hz,2H), 2.27-2.17 (m, 2H), 2.11-2.03 (m, 2H), 1.68 (dq, J=3.0, 12.8 Hz,2H), 1.40 (dq, J=3.3, 12.6 Hz, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.01 (t,J=7.2 Hz, 3H). ESI [M+H]=533.2.

Example 96 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-pyrazol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 121)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 121 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.97 (d, J=2.4 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J=2.4 Hz,1H), 7.41 (dd, J=2.4, 8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.01 (d,J=2.4 Hz, 1H), 4.82-4.74 (m, 1H), 3.45 (tt, J=3.8, 11.5 Hz, 1H),3.05-2.95 (m, 1H), 2.91 (q, J=7.1 Hz, 2H), 2.27-2.18 (m, 2H), 2.10-2.01(m, 2H), 1.68 (dq, J=3.0, 12.8 Hz, 2H), 1.40 (dq, J=3.1, 12.6 Hz, 2H),1.22 (br d, J=6.2 Hz, 6H), 1.04 (t, J=7.3 Hz, 3H). ESI [M+H]=533.2.

Example 97 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyrazin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 122)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 122 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.59 (d, J=2.2 Hz, 1H), 8.26-8.16 (m, 2H), 7.99-7.90 (m,2H), 7.72 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.82 (br s, 1H), 3.52-3.40(m, 1H), 3.06-2.98 (m, 1H), 2.95 (q, J=7.1 Hz, 2H), 2.29-2.18 (m, 2H),2.11-2.01 (m, 2H), 1.70 (dq, J=3.2, 12.8 Hz, 2H), 1.41 (dq, J=3.4, 12.5Hz, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.07 (t, J=7.3 Hz, 3H). ESI[M+H]=545.2.

Example 98 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 123)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 123 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.95 (d, J=4.25 Hz, 1H) 8.56 (d, J=2.38 Hz, 1H) 7.92-8.04(m, 2H) 7.72-7.82 (m, 2H) 7.55 (d, J=8.38 Hz, 1H) 4.76-4.89 (m, 1H)3.40-3.54 (m, 1H) 3.06 (tt, J=12.10, 3.35 Hz, 1H) 2.92 (q, J=7.25 Hz,2H) 2.22-2.35 (m, 2H) 2.00-2.13 (m, 2H) 1.73 (qd, J=12.78, 2.94 Hz, 2H)1.44 (qd, J=12.57, 3.06 Hz, 2H) 1.25 (br d, J=6.13 Hz, 6H) 1.05 (t,J=7.25 Hz, 3H). ESI [M+H]=545.2.

Example 99 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 124)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 124 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.96 (s, 1H), 8.55 (d, J=1.88 Hz, 1H) 8.40 (dd, J=7.13,1.13 Hz, 1H), 8.02 (dd, J=8.32, 2.19 Hz, 1H), 7.81 (s, 1H) 7.60 (d,J=8.38 Hz, 1H), 7.15 (d, J=7.13 Hz, 1H), 4.76-4.90 (m, 1H), 3.42-3.54(m, 1H), 3.01-3.12 (m, 1H), 2.92 (q, J=7.25 Hz, 2H), 2.21-2.32 (m, 2H),2.04-2.14 (m, 2H), 1.73 (qd, J=12.84, 2.88 Hz, 2H), 1.44 (qd, J=12.57,3.06 Hz, 2H), 1.25 (br d, J=6.13 Hz, 6H), 1.05 (t, J=7.25 Hz, 3H). ESI[M+H]=545.2.

Example 100 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyridin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 125)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 125 was prepared. ^(i)H NMR (400 MHz,methanol-d₄) δ=8.28 (d, J=7.3 Hz, 2H), 8.02 (d, J=2.0 Hz, 1H), 7.79 (s,1H), 7.69-7.57 (m, 2H), 7.27 (d, J=7.3 Hz, 2H), 4.85-4.77 (m, 1H), 3.45(tt, J=3.8, 11.5 Hz, 1H), 3.03 (tt, J=3.3, 12.0 Hz, 1H), 2.88 (q, J=7.1Hz, 2H), 2.29-2.20 (m, 2H), 2.11-2.01 (m, 2H), 1.70 (dq, J=3.0, 12.8 Hz,2H), 1.41 (dq, J=3.1, 12.6 Hz, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.01 (t,J=7.3 Hz, 3H). ESI [M+H]=544.2.

Example 101 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyridin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 126)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 126 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.10 (d, J=2.3 Hz, 1H), 7.98 (dd, J=1.1, 5.9 Hz, 1H),7.89 (ddd, J=1.8, 7.2, 8.8 Hz, 1H), 7.70-7.60 (m, 2H), 7.46 (d, J=8.3Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.02-6.93 (m, 1H), 4.74-4.67 (m, 1H),3.36 (tt, J=3.9, 11.6 Hz, 1H), 2.94 (tt, J=3.5, 12.1 Hz, 1H), 2.81 (q,J=7.2 Hz, 2H), 2.20-2.11 (m, 2H), 2.02-1.94 (m, 2H), 1.61 (dq, J=3.1,12.9 Hz, 2H), 1.38-1.26 (m, 2H), 1.13 (d, J=6.1 Hz, 6H), 0.94 (t, J=7.2Hz, 3H). ESI [M+H]=544.2.

Example 102 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyrimidin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 127)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 127 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.66 (d, J=2.3 Hz, 1H), 8.53 (d, J=4.8 Hz, 2H), 7.97 (dd,J=2.3, 8.4 Hz, 1H), 7.79 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.91 (t, J=4.9Hz, 1H), 4.87-4.80 (m, 1H), 3.48 (tt, J=3.8, 11.5 Hz, 1H), 3.11-3.02 (m,1H), 2.99 (q, J=7.3 Hz, 2H), 2.31-2.21 (m, 2H), 2.14-2.05 (m, 2H), 1.72(dq, J=2.9, 12.8 Hz, 2H), 1.43 (dq, J=3.2, 12.6 Hz, 2H), 1.25 (br d,J=6.1 Hz, 6H), 1.10 (t, J=7.3 Hz, 3H). ESI [M+H]=545.2.

Example 103 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(pyridin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 128)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 128 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.54 (d, J=2.63 Hz, 1H), 8.30 (d, J=5.50 Hz, 1H),8.22-8.27 (m, 1H), 7.90-7.96 (m, 2H), 7.78 (s, 1H), 7.51-7.59 (m, 2H),4.82-4.88 (m, 1H), 3.42-3.52 (m, 1H), 3.06 (tt, J=12.04, 3.53 Hz, 1H),2.90 (q, J=7.17 Hz, 2H), 2.20-2.34 (m, 2H), 2.03-2.17 (m, 2H), 1.74-1.75(m, 2H) 1.38-1.51 (m, 2H), 1.25 (d, J=6.13 Hz, 6H), 1.04 (t, J=7.25 Hz,3H). ESI [M+H]=544.2.

Example 104 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isopropyl-1H-pyrazol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 129)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 129 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.74 (s, 1H), 7.61 (d, J=1.75 Hz, 1H), 7.49 (d, J=2.50Hz, 1H), 7.34 (d, J=8.38 Hz, 1H), 7.04 (dd, J=8.32, 2.44 Hz, 1H, 6.18(d, J=2.00 Hz, 1H), 4.77-4.87 (m, 1H), 4.62 (dt, J=13.35, 6.64 Hz, 1H),3.40-3.53 (m, 1H), 3.06 (tt, J=12.07, 3.38 Hz, 1H), 2.87 (q, J=7.25 Hz,2H), 2.19-2.31 (m, 2H), 2.02-2.17 (m, 2H), 1.72 (qd, J=12.82, 2.81 Hz,2H), 1.46 (d, J=6.63 Hz, 8H), 1.24 (br d, J=6.13 Hz, 6H), 1.02 (t,J=7.25 Hz, 3H). ESI [M+H]=575.2.

Example 105 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[4-hydroxypiperidin-1-yl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 130)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 130 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.79 (s, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.35 (d, J=8.6 Hz,1H), 7.22 (dd, J=2.4, 8.6 Hz, 1H), 4.81 (br s, 1H), 3.85 (tt, J=4.0, 8.5Hz, 1H), 3.80-3.65 (m, 2H), 3.45 (tdd, J=3.8, 7.5, 11.2 Hz, 1H),3.20-3.00 (m, 3H), 2.87 (q, J=7.2 Hz, 2H), 2.24 (br d, J=12.6 Hz, 2H),2.08 (br d, J=10.4 Hz, 2H), 1.99 (br dd, J=3.6, 9.4 Hz, 2H), 1.79-1.56(m, 4H), 1.47-1.34 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H), 1.02 (t, J=7.2Hz, 3H). ESI [M+H]=551.2.

Example 106 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-hydroxyethyl)(methyl))amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (Compound 131)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 131 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.68 (s, 1H), 7.38 (d, J=2.9 Hz, 1H), 7.27 (d, J=8.6 Hz,1H), 6.95 (dd, J=2.9, 8.6 Hz, 1H), 4.82-4.78 (m, 1H), 3.80-3.70 (m, 2H),3.67-3.54 (m, 2H), 3.51-3.40 (m, 1H), 3.09 (s, 3H), 3.02 (tt, J=3.4,12.0 Hz, 1H), 2.87 (q, J=7.1 Hz, 2H), 2.31-2.15 (m, 2H), 2.10-2.00 (m,2H), 1.69 (dq, J=2.9, 12.9 Hz, 2H), 1.41 (dq, J=3.2, 12.6 Hz, 2H), 1.22(br d, J=6.2 Hz, 6H), 1.02 (t, J=7.3 Hz, 3H). ESI [M+H]=525.2.

Example 107 Preparation of isopropyl(trans-4-(5-(2-(N-ethylsulfamoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 60)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 60 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.37 (d, J=2.3 Hz, 1H), 7.89-7.73 (m, 2H), 7.54 (d, J=0.9Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.03 (s, 1H), 4.85 (br s, 1H),3.54-3.45 (m, 1H), 3.15-3.02 (m, 1H), 2.96 (q, J=7.3 Hz, 2H), 2.27 (brd, J=12.1 Hz, 2H), 2.10 (br d, J=10.6 Hz, 2H), 1.81-1.67 (m, 2H),1.49-1.36 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.09 (t, J=7.2 Hz, 3H).ESI [M+H]=534.2.

Example 108 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-methoxyethyl)(methyl))amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (Compound 132)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 132 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.68 (s, 1H), 7.40 (d, J=2.6 Hz, 1H), 7.29 (d, J=8.6 Hz,1H), 6.97 (dd, J=2.7, 8.6 Hz, 1H), 3.71-3.57 (m, 4H), 3.47 (br t, J=11.6Hz, 1H), 3.37 (s, 3H), 3.09 (s, 3H), 3.06-2.97 (m, 1H), 2.94-2.85 (m,2H), 2.25 (br d, J=12.6 Hz, 2H), 2.14-2.03 (m, 2H), 1.78-1.64 (m, 2H),1.49-1.35 (m, 2H), 1.25 (br d, J=6.0 Hz, 6H), 1.08-1.01 (m, 3H). ESI[M+H]=539.2.

Example 109 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[1,1-dioxidothiomorpholino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 133)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 133 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.73 (s, 1H), 7.67-7.63 (m, 1H), 7.41 (d, J=8.4 Hz, 1H),7.29 (dd, J=2.8, 8.6 Hz, 1H), 4.87-4.81 (m, 1H), 4.02 (br s, 4H),3.53-3.42 (m, 1H), 3.20 (br s, 4H), 3.05 (ddd, J=3.5, 8.7, 12.1 Hz, 1H),2.88 (q, J=7.2 Hz, 2H), 2.26 (br d, J=12.5 Hz, 2H), 2.09 (br d, J=11.0Hz, 2H), 1.79-1.65 (m, 2H), 1.50-1.38 (m, 2H), 1.25 (br d, J=6.1 Hz,6H), 1.04 (t, J=7.3 Hz, 3H). ESI [M+H]=585.2.

Example 110 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[morpholino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 134)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 134 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.74 (br s, 1H), 7.57 (br s, 1H), 7.34 (br d, J=7.9 Hz,1H), 7.17 (br d, J=7.3 Hz, 1H), 4.82-4.74 (m, 1H), 3.85 (br s, 4H), 3.45(br s, 1H), 3.28 (br s, 4H), 3.01 (br s, 1H), 2.85 (q, J=7.2 Hz, 2H),2.24 (br d, J=12.6 Hz, 2H), 2.07 (br d, J=10.6 Hz, 2H), 1.68 (br s, 2H),1.49-1.34 (m, 2H), 1.22 (br d, J=6.0 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H).ESI [M+H]=537.2.

Example 111 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[piperidin-1-yl]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 135)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 135 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.76 (s, 1H), 7.66 (br s, 1H), 7.45-7.33 (m, 1H), 7.26(br d, J=7.1 Hz, 1H), 4.86-4.79 (m, 1H), 3.53-3.46 (m, 1H), 3.41 (br s,4H), 3.07 (br t, J=11.4 Hz, 1H), 2.88 (q, J=7.1 Hz, 2H), 2.26 (br d,J=12.7 Hz, 2H), 2.10 (br d, J=11.0 Hz, 2H), 1.86-1.63 (m, 8H), 1.50-1.36(m, 2H), 1.24 (br d, J=5.7 Hz, 6H), 1.04 (br t, J=7.2 Hz, 3H). ESI[M+H]=535.2.

Example 112 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-isopropylpyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 136)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 136 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.83 (br s, 1H), 8.30 (d, J=7.21 Hz, 1H), 7.90 (dd,J=2.20, 8.31 Hz, 1H), 7.77-7.83 (m, 1H), 7.60 (d, J=8.31 Hz, 1H), 7.01(d, J=7.09 Hz, 1H), 4.81-4.85 (m, 1H), 3.48 (tt, J=3.88, 11.58 Hz, 1H),3.21 (spt, J=6.83 Hz, 1H), 3.05 (tt, J=3.50, 12.03 Hz, 1H), 2.87 (q,J=7.21 Hz, 2H), 2.28 (br d, J=12.35 Hz, 2H), 2.10 (br d, J=9.90 Hz, 2H),1.73 (dq, J=2.93, 12.92 Hz, 2H), 1.47 (d, J=6.85 Hz, 6H), 1.29-1.45 (m,2H), 1.25 (br d, J=6.11 Hz, 6H), 1.01 (t, J=7.21 Hz, 3H). ESI[M+H]=587.1.

Example 113 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(oxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 137)

Following the same protocol and under the same reaction conditions asfor Compound 111, Compound 137 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=7.53 (s, 1H), 7.25 (t, J=5.7 Hz, 1H), 7.19-7.11 (m, 2H), 7.04 (d,J=2.4 Hz, 1H), 6.99 (br d, J=7.7 Hz, 1H), 6.62 (dd, J=2.4, 8.4 Hz, 1H),4.85 (t, J=6.5 Hz, 2H), 4.72 (td, J=6.2, 12.5 Hz, 1H), 4.57 (sxt, J=6.4Hz, 1H), 4.45-4.38 (m, 2H), 3.30-3.22 (m, 1H), 2.90-2.80 (m, 1H),2.80-2.72 (m, 2H), 2.10 (br d, J=11.2 Hz, 2H), 1.89 (br d, J=10.1 Hz,2H), 1.61-1.44 (m, 2H), 1.39-1.21 (m, 2H), 1.14 (d, J=6.4 Hz, 6H), 0.95(t, J=7.2 Hz, 3H). ESI [M+H]=523.2.

Example 114 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-isopropylimidazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 138)

a) Synthesis of 1-isopropyl-5-nitro-1H-imidazole

To a solution of 5-nitro-1H-imidazole (15 g, 133 mmol, 1.0 eq.) in DMF(50 mL) was added K₂CO₃ (55 g, 398 mmol, 3.0 eq.) and 2-iodopropane(24.81 g, 146 mmol, 1.1 eq.). The mixture was stirred at 65° C. for 12h. The reaction was filtered and filtrate was concentrated under reducedpressure. The residue was purified by prep-HPLC (neutral condition;column: Phenomenex luna C18 250*80 mm*10 um; mobile phase: [water(0.1%TFA)-ACN]; B %: 5%-30%,20 min) to yield 1-isopropyl-5-nitro-1H-imidazole(1.7 g, 11 mmol, 8% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=8.19 (s, 1H), 8.11 (s, 1H), 5.33 (br d, J=6.8 Hz, 1H), 1.63 (br d,J=6.6 Hz, 6H). ESI [M+H]=156.1.

b) Synthesis of 3-isopropylimidazol-4-amine

A mixture of 1-isopropyl-5-nitro-1H-imidazole (200 mg, 1 mmol, 1.0 eq.),Fe (360 mg, 6 mmol, 5 eq.), NH₄Cl (207 mg, 4 mmol, 3.0 eq.) in THF (10mL), EtOH (10 mL) and H₂O (3 mL) was stirred at 80° C. for 2 h under N₂atmosphere. The reaction was filtered, then the filter was concentratedunder reduced pressure. The residue was diluted with H₂O 20 mL andextracted with EtOAc 90 mL (30 mL×3). The combined organic layers driedover Na₂SO₄, filtered and concentrated under reduced pressure to yield3-isopropylimidazol-4-amine (150 mg, crude) as a black oil. ESI[M+H]=126.1.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-isopropylimidazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 138)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate,using General Method F. ¹H NMR (400 MHz, methanol-d₄) δ=9.12 (s, 1H),7.69 (s, 1H), 7.59 (s, 1H), 7.48 (d, J=2.38 Hz, 1H), 7.38 (d, J=8.38 Hz,1H), 7.05 (dd, J=8.25, 2.38 Hz, 1H), 4.78-4.83 (m, 1H), 4.61 (dt,J=13.41, 6.61 Hz, 1H), 3.46 (qd, J=7.61, 3.56 Hz, 1H), 3.02 (ddd,J=11.88, 8.69, 3.44 Hz, 1H), 2.84 (q, J=7.21 Hz, 2H), 2.25 (br d,J=12.26 Hz, 2H), 2.09 (br d, J=10.38 Hz, 2H), 1.65-1.77 (m, 2H), 1.58(d, J=6.63 Hz, 6H), 1.39-1.48 (m, 2H), 1.24 (br d, J=6.00 Hz, 6H), 1.01(t, J=7.19 Hz, 3H). ESI [M+H]=575.1.

Example 115 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isopropyl-1H-imidazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 139)

a) Synthesis of 1-isopropylimidazol-4-amine

To a solution of 1-isopropyl-4-nitro-imidazole (1.0 g, 6.5 mmol, 1.0eq.) in EtOAc (50 mL) was added Pd/C (0.1 g, 10% purity) and the mixturewas stirred under H₂ (15 psi) at 25° C. for 3 h, and then filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (TFA condition). column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 1%-10%,10 min to yield1-isopropylimidazol-4-amine (390 mg, 3.12 mmol, 48% yield) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ=7.91-7.77 (m, 1H), 6.34-6.23 (m, 1H),4.42-4.30 (m, 1H), 1.53 (d, J=6.7 Hz, 6H). ESI [M+H]=126.1.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isopropyl-1H-imidazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 139)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 1-isopropylimidazol-4-amine, using General Method F. ¹H NMR (400MHz, methanol-d₄) δ=8.91-8.86 (m, 1H), 7.70 (s, 1H), 7.63-7.59 (m, 2H),7.42-7.37 (m, 1H), 7.18-7.12 (m, 1H), 4.87-4.81 (m, 1H), 4.73-4.62 (m,1H), 3.54-3.43 (m, 1H), 3.03 (tt, J=3.5, 12.0 Hz, 1H), 2.86 (q, J=7.2Hz, 2H), 2.31-2.21 (m, 2H), 2.13-2.04 (m, 2H), 1.77-1.67 (m, 2H),1.65-1.61 (m, 6H), 1.49-1.39 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H),1.07-0.98 (m, 3H). ESI [M+H]=575.3.

Example 116 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropylpyrazin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 140)

a) Synthesis of 6-isopropenylpyrazin-2-amine

A mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0g, 6.0 mmol, 1.3 eq.), 6-bromopyrazin-2-amine (820 mg, 5 mmol, 1.0 eq.),Cs₂CO₃ (4.6 g, 14 mmol, 3.0 eq.) and Pd(dppf)Cl₂ (345 mg, 471 umol, 0.1eq.) in dioxane (20 mL) and H₂O (10 mL) was stirred at 80° C. for 12 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure. The residue was diluted with H₂O 20 mL and extracted withEtOAc 90 mL (30 mL×3). The combined organic layers dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography (SiO₂, petroleum ether:ethylacetate=10:1 to 5:1 to 3:1 to 1:1 to 0:1) to yield6-isopropenylpyrazin-2-amine (730 mg, crude) as a white solid. ¹H NMR(400 MHz, methanol-d₄) δ=7.91 (s, 1H), 7.79 (s, 1H), 5.87 (s, 1H), 5.29(s, 1H), 2.14 (s, 3H). ESI [M+H]=136.1.

b) Synthesis of 6-isopropylpyrazin-2-amine

To a solution of 6-isopropenylpyrazin-2-amine (700 mg, 5 mmol, 1 eq.) inEtOAc (20 mL) was added AcOH (31 mg, 518 umol, 0.1 eq.) and Pd/C (100mg, 10% purity). The mixture was stirred under H₂ (15 psi) at 30° C. for12 h. The mixture was filtered, the filter liquor was concentrated underreduced pressure. The residue was purified by prep-HPLC (column:Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water(10 mMNH₄HCO₃)-ACN]; B %: 1%-30%,10 min) to yield 6-isopropylpyrazin-2-amine(300 mg) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.73 (s, 1H)7.63 (s, 1H) 2.82-2.92 (m, 1H) 1.27 (d, J=6.88 Hz, 6H). ESI [M+H]=138.2.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropylpyrazin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 140)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 6-isopropylpyrazin-2-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.84 (d, J=2.25 Hz, 1H), 8.03 (s, 1H), 7.94 (dd, J=8.38,2.25 Hz, 1H), 7.90 (s, 1H), 7.72 (s, 1H) 7.43 (d, J=8.38 Hz, 1H),4.81-4.85 (m, 1H), 3.41-3.55 (m, 1H), 2.99-3.13 (m, 2H), 2.90 (q, J=7.13Hz, 2H), 2.27 (br d, J=12.26 Hz, 2H), 2.10 (br d, J=10.51 Hz, 2H),1.66-1.77 (m, 2H), 1.42-1.51 (m, 2H), 1.39 (d, J=6.88 Hz, 6H), 1.25 (brd, J=6.13 Hz, 6H), 1.03 (t, J=7.19 Hz, 3H). ESI [M+H]=587.1.

Example 117 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-methyl-1H-imidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 141)

a) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-guanidino-phenyl]thiazol-2-yl]cyclohexyl]carbamate

To a solution of isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(0.5 g, 1 mmol, 1 eq.) in HCl (10 mL) was added cyanamide (180 mg, 2mmol, 2 eq.). The mixture was stirred at 60° C. for 6 h, and thenfiltered. The residue was purified by prep-HPLC (TFA condition). column:Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water(0.1%TFA)-ACN]; B %: 20%-50%,10 min to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-guanidino-phenyl]thiazol-2-yl]cyclohexyl]carbamate(0.31 g, 497.85 umol, 46% yield, TFA salt) as a white solid. 1H NMR (400MHz, methanol-d₄) δ=8.04-7.94 (m, 1H), 7.82-7.74 (m, 1H), 7.64-7.55 (m,2H), 4.84-4.75 (m, 1H), 3.55-3.40 (m, 1H), 3.14-3.02 (m, 1H), 2.94-2.83(m, 2H), 2.33-2.23 (m, 2H), 2.12-2.04 (m, 2H), 1.80-1.64 (m, 2H),1.56-1.38 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.08-0.98 (m, 3H). ESI[M+H]=509.1.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-methyl-1H-imidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 141)

To a solution of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-guanidino-phenyl]thiazol-2-yl]cyclohexyl]carbamate(136 mg, 219 umol, 1.5 eq., TFA), TEA (44 mg, 438 umol, 3 eq.) in DMF (3mL) was added 1-bromopropan-2-one (20 mg, 146 umol, 1 eq.). The mixturewas stirred at 25° C. for 5 h. The residue was purified by prep-HPLC(TFA condition). column: Phenomenex Luna C18 100*30 mm*5 um; mobilephase: [water(0.1% TFA)-ACN]; B %: 10%-40%,12 min to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-methyl-1H-imidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(98% purity, TFA salt) (15 mg) as a pale yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.22-8.08 (m, 1H), 7.86-7.70 (m, 3H), 6.89-6.75 (m, 1H),5.01-4.90 (m, 1H), 3.53-3.41 (m, 1H), 3.11-3.01 (m, 1H), 2.92 (q, J=7.1Hz, 2H), 2.34-2.20 (m, 5H), 2.10 (br d, J=10.6 Hz, 2H), 1.80-1.64 (m,2H), 1.51-1.36 (m, 2H), 1.25 (br d, J=6.0 Hz, 6H), 1.13-0.97 (m, 3H).ESI [M+H]=547.1.

Example 118 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropyl-1H-imidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 142)

Following the same protocol and under the same reaction conditions asfor Compound 141, Compound 142 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.26-8.14 (m, 1H), 7.85-7.80 (m, 2H), 7.77-7.73 (m, 1H),6.93-6.85 (m, 1H), 4.85-4.81 (m, 1H), 3.53-3.39 (m, 1H), 3.14-2.98 (m,1H), 2.97-2.85 (m, 3H), 2.33-2.24 (m, 2H), 2.13-2.05 (m, 2H), 1.80-1.63(m, 2H), 1.51-1.37 (m, 2H), 1.33 (d, J=6.8 Hz, 6H), 1.25 (br d, J=6.1Hz, 6H), 1.10-0.99 (m, 3H). ESI [M+H]=575.1.

Example 119 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropylpyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 143)

a) Synthesis of 6-isopropenylpyridazin-3-amine

A mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.16g, 7 mmol, 1.2 eq.), 6-bromopyridazin-3-amine (1 g, 6 mmol, 1 eq.),Cs₂CO₃ (5.6 g, 17 mmol, 3 eq.), Pd(dppf)Cl₂ (421 mg, 575 umol, 0.1 eq.)in dioxane (20 mL)/H₂O (10 mL) was stirred at 80° C. for 12 h under N₂atmosphere, and then concentrated under reduced pressure to give aresidue which was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=10:1 to 0:1) to yield 6-isopropenylpyridazin-3-amine(550 mg, 4 mmol, 71% yield) as a pale yellow solid. ESI [M+H]=136.1.

b) Synthesis of 6-isopropylpyridazin-3-amine

To a solution of 6-isopropenylpyridazin-3-amine (540 mg, 4 mmol, 1 eq.)and AcOH (24 mg, 400 umol, 0.1 eq.) in EtOAc (30 mL) was added Pd/C (50mg, 10% purity) and the mixture was stirred under H₂ (15 psi) at 25° C.for 12 h. The reaction mixture was filtered and concentrated underreduced pressure to give a residue which was purified by prep-HPLC(neutral condition). column: Waters Xbridge Prep OBD C18 150*40 mm*10um: mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %: 1%-15%,8 min to yield6-isopropylpyridazin-3-amine (300 mg, 2 mmol, 55% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ=7.18-7.09 (m, 1H), 6.78-6.69 (m, 1H),4.91-4.66 (m, 2H), 3.27-3.10 (m, 1H), 1.30 (d, J=7.0 Hz, 6H). ESI[M+H]=138.2.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropylpyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 143)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand 6-isopropylpyridazin-3-amine, using General Method F. ¹H NMR (400MHz, methanol-d₄) δ=8.63-8.49 (m, 1H), 7.99-7.94 (m, 1H), 7.93-7.88 (m,1H), 7.75 (s, 1H), 7.62-7.55 (m, 1H), 7.50 (d, J=8.3 Hz, 1H), 4.86-4.82(m, 1H), 3.48 (tt, J=3.8, 11.5 Hz, 1H), 3.31-3.25 (m, 1H), 3.10-2.98 (m,1H), 2.91 (q, J=7.2 Hz, 2H), 2.31-2.23 (m, 2H), 2.14-2.06 (m, 2H),1.79-1.66 (m, 2H), 1.50-1.43 (m, 2H), 1.42 (d, J=7.0 Hz, 6H), 1.25 (brd, J=6.2 Hz, 6H), 1.07-0.98 (m, 3H). ESI [M+H]=587.1.

Example 120 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[1-(2-methylpropanoyl)azetidin-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 146)

a) Synthesis of tert-butyltrans-3-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxy-carbonylamino)cyclohexyl]thiazol-5-yl]anilino]azetidine-1-carboxylate

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand tert-butyl 3-aminoazetidine-1-carboxylate, using General Method F.ESI [M+H]=622.2.

b) Synthesis of isopropyltrans-N-[4-[5-[4-(azetidin-3-ylamino)-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 144)

A mixture oftert-butyltrans-3-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonyl-amino)cyclohexyl]thiazol-5-yl]anilino]azetidine-1-carboxylate(100 mg, 161 umol, 1 eq.) in HCl/MeOH (2 mL) (4 M) was stirred at 25° C.for 30 min under N₂ atmosphere. The reaction mixture was concentratedunder reduced pressure to yield isopropyltrans-N-[4-[5-[4-(azetidin-3-ylamino)-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(89.76 mg, crude, HCl salt) as a yellow oil. ¹H NMR (400 MHz,methanol-d₄) δ=7.73 (s, 1H), 7.30 (dd, J=2.8, 5.0 Hz, 2H), 6.90-6.71 (m,1H), 4.88-4.77 (m, 1H), 4.71-4.56 (m, 1H), 4.46 (br t, J=8.9 Hz, 2H),4.15-3.97 (m, 2H), 3.47 (br t, J=11.6 Hz, 1H), 3.07 (br t, J=12.0 Hz,1H), 2.87 (q, J=7.2 Hz, 2H), 2.25 (br d, J=12.2 Hz, 2H), 2.09 (br d,J=10.9 Hz, 2H), 1.78-1.59 (m, 2H), 1.52-1.35 (m, 2H), 1.24 (br d, J=5.9Hz, 6H), 1.03 (br t, J=7.2 Hz, 3H). ESI [M+H]=522.2.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isobutyl-azetidin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 145)

To a solution of isopropyltrans-N-[4-[5-[4-(azetidin-3-ylamino)-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate (89 mg, 159 umol, 1.0 eq., HClsalt) in DCE (2 mL) was added AcOH (1 mg, 16 umol, 0.1 eq.),2-methylpropanal (11.50 mg, 159 umol, 1.0 eq.), NaBH(OAc)₃ (101 mg, 478umol, 3.0 eq.) at 0° C. The mixture was stirred at 25° C. for 2 h. Thereaction mixture was concentrated under reduced pressure. The residuewas purified by prep-HPLC (neutral condition; column: Waters Xbridge BEHC18 100*30 mm*10 um; mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %:45%-75%,10 min) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isobutylazetidin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(80 mg, 138 umol, 86.8% yield) as a yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ=7.62 (s, 1H), 7.33-7.22 (m, 2H), 6.86-6.71 (m, 1H), 4.80(br d, J=6.0 Hz, 1H), 4.77-4.65 (m, 1H), 4.55 (br d, J=7.1 Hz, 1H), 4.44(br s, 1H), 4.25 (br s, 1H), 3.99 (br d, J=9.5 Hz, 1H), 3.51-3.35 (m,1H), 3.24-3.09 (m, 2H), 3.06-2.92 (m, 1H), 2.82 (q, J=7.1 Hz, 2H), 2.22(br d, J=11.9 Hz, 2H), 2.06 (br d, J=10.4 Hz, 2H), 2.02-1.91 (m, 1H),1.78-1.59 (m, 2H), 1.49-1.31 (m, 2H), 1.22 (d, J=6.2 Hz, 6H), 1.02 (d,J=6.6 Hz, 6H), 0.99 (t, J=7.3 Hz, 3H). ESI [M+H]=578.2.

d) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-[[1-(2-methylpropanoyl)azetidin-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 146)

To a solution of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isobutylazetidin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(30 mg, 52 umol, 1.0 eq.) in DCM (2 mL) was added KMnO₄ (25 mg, 156umol, 3.0 eq.) and benzyltriethylammonium chloride (35 mg, 156 umol, 3eq.). The mixture was stirred at 0° C. for 0.5 h. The reaction wasquenched with sat.aq. Na₂SO₃ 20 mL and extracted with DCM 20 mL (10mL×2). The combined organic layers were dried with Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byprep-HPLC (TFA condition; column: Phenomenex Luna C18 150*30 mm*5 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 45%-75%,10 min) to yieldisopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[1-(2-methylpropanoyl)azetidin-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(6.1 mg, 9.6 umol, 18% yield, 92.8% purity) as a pale yellow solid. ¹HNMR (400 MHz, methanol-d₄) δ=7.64 (s, 1H), 7.24 (dd, J=2.9, 5.3 Hz, 2H),6.76 (dd, J=2.4, 8.4 Hz, 1H), 4.83-4.75 (m, 1H), 4.70-4.59 (m, 1H),4.42-4.29 (m, 2H), 4.10-3.96 (m, 1H), 3.88-3.73 (m, 1H), 3.51-3.35 (m,1H), 2.99 (br t, J=12.0 Hz, 1H), 2.85 (q, J=7.3 Hz, 2H), 2.57 (td,J=6.6, 13.5 Hz, 1H), 2.22 (br d, J=12.8 Hz, 2H), 2.06 (br d, J=10.8 Hz,2H), 1.76-1.60 (m, 2H), 1.47-1.33 (m, 2H), 1.22 (br d, J=6.0 Hz, 6H),1.08 (dd, J=5.1, 6.6 Hz, 6H), 1.01 (t, J=7.3 Hz, 3H). ESI [M+H]=592.1.

Example 121 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-methylazetidin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 147)

a) Synthesis of tert-butyltrans-3-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxy-carbonylamino)cyclohexyl]thiazol-5-yl]anilino]-3-methyl-azetidine-1-carboxylate

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand tert-butyl 3-amino-3-methylazetidine-1-carboxylate, using GeneralMethod F. ESI [M+H]=636.2.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-methylazetidin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 147)

A solution of tert-butyltrans-3-[3-(ethylsulfamoyl)-4-[2-[4-(isopropoxycarbonyl-amino)cyclohexyl]thiazol-5-yl]anilino]-3-methyl-azetidine-1-carboxylate(150 mg, 236 umol, 1 eq.) in HCl/MeOH (2 mL, 4M) was stirred at 25° C.for 2 h. The reaction was concentrated. The residue was purified byprep-HPLC (TFA condition: column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water(0.1% TFA)-ACN]; B %: 15%-45%,10 min) to yieldisopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-methylazetidin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(6.7 mg, 10 umol, 4.3% yield, 99.4% purity, TFA) as a pale yellow solid.¹H NMR (400 MHz, methanol-d₄) δ=7.70-7.66 (m, 1H), 7.30 (d, J=8.4 Hz,1H), 7.22 (d, J=2.5 Hz, 1H), 6.71 (dd, J=2.4, 8.3 Hz, 1H), 4.85 (br s,1H), 4.25-4.14 (m, 4H), 3.47 (ddd, J=4.1, 7.7, 11.5 Hz, 1H), 3.04 (br t,J=12.0 Hz, 1H), 2.86 (q, J=7.1 Hz, 2H), 2.25 (br d, J=12.3 Hz, 2H),2.13-2.03 (m, 2H), 1.76-1.66 (m, 5H), 1.43 (dq, J=3.0, 12.5 Hz, 2H),1.28-1.20 (m, 6H), 1.03 (t, J=7.2 Hz, 3H). ESI [M+H]=536.2.

Example 122 Preparation of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 148)

a) Synthesis of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-[[1-(2-trimethylsilylethoxymethyl)-1H-imidazol-2-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

From isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-bromo-phenyl]thiazol-2-yl]cyclohexyl]carbamateand 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-amine, usingGeneral Method F. ESI [M+H]=675.3.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 148)

From isopropyltrans-N-[4-[5-[2-(azetidin-1-ylsulfonyl)-4-[[1-(2-trimethylsilylethoxy-methyl)-1H-imidazol-2-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate,using General Method I. ¹H NMR (400 MHz, methanol-d₄) δ=7.89 (d, J=2.2Hz, 1H), 7.71 (s, 1H), 7.62-7.48 (m, 2H), 7.11 (s, 2H), 4.84-4.76 (m,1H), 3.68 (t, J=7.7 Hz, 4H), 3.54-3.38 (m, 1H), 3.04 (tt, J=3.5, 12.1Hz, 1H), 2.27-2.17 (m, 2H), 2.17-2.09 (m, 2H), 2.07 (br d, J=10.8 Hz,2H), 1.70 (dq, J=2.9, 12.8 Hz, 2H), 1.41 (dq, J=3.1, 12.6 Hz, 2H), 1.22(br d, J=6.2 Hz, 6H). ESI [M+H]=545.2.

Example 123 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(2H-triazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 149)

a) Synthesis of trimethyl-[2-[(4-nitrotriazol-2-yl)methoxy]ethyl]silane

To a solution of 4-nitro-2H-triazole (1 g, 8.7 mmol, 1 eq.) in THF (20mL) was added SEM-Cl (1.75 g, 10.5 mmol, 1.2 eq.) and NaH (385 mg, 9.6mmol, 60% in oil, 1.1 eq.) at 0° C. The mixture was stirred at 25° C.for 12 h. The reaction mixture was quenched by sat.aq. NH₄Cl (10 mL) at0° C., and then extracted with ethyl acetate (60 mL) (20 mL×3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue, which waspurified by MPLC (SiO₂, petroleum ether:ethyl acetate=50:1 to 10:1) toyield trimethyl-[2-[(4-nitrotriazol-2-yl)methoxy]ethyl]silane (0.76 g,3.1 mmol, 35% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃)δ=8.30-8.21 (m, 1H), 5.67-5.56 (m, 2H), 3.79-3.68 (m, 2H), 1.01-0.92 (m,2H), 0.05-0.05 (m, 9H).

b) Synthesis of 2-(2-trimethylsilylethoxymethyl)triazol-4-amine

To a solution of trimethyl-[2-[(4-nitrotriazol-2-yl)methoxy]ethyl]silane(0.76 g, 3.1 mmol, 1 eq.) in ethyl acetate (20 mL) was added Pd/C (0.05g, 10% purity). The mixture was stirred under H₂ (15 psi) at 25° C. for12 h. The reaction mixture was filtered and concentrated under reducedpressure to give a residue, which was purified by prep-HPLC (neutralcondition: column: Welch Xtimate C18 150*30 mm*5 um; mobile phase:[water(10 mM NH₄HCO₃)-ACN]; B %: 20%-50%,8 min) to yield2-(2-trimethylsilyl-ethoxymethyl)triazol-4-amine (0.3 g, 1.4 mmol, 45%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=7.17-7.03 (m, 1H),5.55-5.43 (m, 2H), 3.86-3.73 (m, 2H), 3.68-3.54 (m, 2H), 1.00-0.82 (m,2H), 0.00 (s, 9H). ESI [M+H]=215.1.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[2-(2-trimethyl-silylethoxymethyl)triazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand 2-(2-trimethylsilyl-ethoxymethyl)triazol-4-amine, using GeneralMethod F. ESI [M+H]=664.3.

d) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(2H-triazol-4-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 149)

From isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[2-(2-trimethyl-silylethoxy-methyl)triazol-4-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate,using General Method I. ¹H NMR (400 MHz, methanol-d₄) δ=8.15-8.03 (m,1H), 7.80-7.71 (m, 1H), 7.58-7.50 (m, 1H), 7.49-7.44 (m, 1H), 7.41-7.33(m, 1H), 4.80-4.71 (m, 1H), 3.54-3.42 (m, 1H), 3.12-3.03 (m, 1H),2.99-2.90 (m, 2H), 2.33-2.23 (m, 2H), 2.16-2.03 (m, 2H), 1.81-1.66 (m,2H), 1.52-1.36 (m, 2H), 1.34-1.20 (m, 6H), 1.12-1.05 (m, 3H). ESI[M+H]=534.2.

Example 124 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[1H-imidazol-2-yl(methyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 150)

a) Synthesis of trimethyl-[2-[(2-nitroimidazol-1-yl)methoxy]ethyl]silane

A mixture of 2-nitro-1H-imidazole (9 g, 79.5 mmol, 1 eq.), NaH (9.55 g,238.7 mmol, 60% purity, 3 eq.) in THF (150 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 0° C. for 30min under N₂ atmosphere, then to the mixture was added2-(chloromethoxy)ethyl-trimethyl-silane (15.92 g, 95.5 mmol, 16.9 mL,1.2 eq.) at 0° C. The mixture was stirred at 25° C. for 2 h. Thereaction mixture was quenched by pouring into sat.aq. NH₄Cl 50 mL at 0°C. and then diluted with H₂O (50 mL) and extracted with ethyl acetate450 mL (150 mL×3). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue,which was purified by column chromatography (SiO₂, petroleum ether:ethylacetate=10:1 to 2:1) to yieldtrimethyl-[2-[(2-nitroimidazol-1-yl)methoxy]ethyl]silane (13 g, 53.4mmol, 67% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=7.34 (d,J=0.88 Hz, 1H), 7.18 (d, J=0.88 Hz, 1H), 5.78 (s, 2H) 3.59-3.72 (m, 2H),0.87-1.04 (m, 2H), 0.04-0.02 (m, 9H).

b) Synthesis of 1-(2-trimethylsilylethoxymethyl)imidazol-2-amine

A mixture of trimethyl-[2-[(2-nitroimidazol-1-yl)methoxy]ethyl]silane (4g, 16.44 mmol, 1 eq.), Pd/C (200 mg, 10% purity), in ethyl acetate (20mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 25° C. for 3 h under H₂ atmosphere. The reaction wasfiltered and the filtrate was concentrated under reduced pressure togive a residue which was purified by prep-HPLC (column: Welch XtimateC18 250*50 mm*10 um; mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %:20%-50%,23 min) to yield1-(2-trimethylsilylethoxymethyl)imidazol-2-amine (3.1 g, 14.5 mmol, 88%yield) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ=6.67 (d, J=1.63Hz, 1H), 6.48 (d, J=1.75 Hz, 1H), 5.13 (s, 2H), 3.46-3.61 (m, 2H),0.84-0.96 (m, 2H), 0.00 (s, 9H). ESI [M+H]=214.2.

c) Synthesis ofN-methyl-1-(2-trimethylsilylethoxymethyl)imidazol-2-amine

A solution of 1-(2-trimethylsilylethoxymethyl)imidazol-2-amine (2 g, 9.3mmol, 1 eq.) in diethoxymethoxyethane (20 mL) was stirred at 100° C. for3 h. The reaction mixture was concentrated under reduced pressure. Theresidue was dissolved in EtOH (20 mL) and NaBH₄ (1.06 g, 28.1 mmol, 3eq.) was added to the solution in portions at 0° C. and stirred at 80°C. for 2 h. The reaction mixture was quenched with H₂O (10 mL) at 30°C., the reaction mixture was concentrated under reduced pressure toremove solvent, and then the mixture was diluted with H₂O (20 mL) andextracted with ethyl acetate 90 mL (30 mL×3). The combined organiclayers dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue which was purified by prep-HPLC (column:Agela DuraShell C18 250*25 mm*10 um; mobile phase: [water(10 mMNH₄HCO₃)-ACN]; B %: 5%-33%,22 min) to yieldN-methyl-1-(2-trimethylsilylethoxy-methyl)imidazol-2-amine (470 mg, 2.0mmol, 22% yield) as a pale yellow oil. ¹H NMR (400 MHz, methanol-d₄)δ=6.69 (d, J=1.71 Hz, 1H), 6.44-6.57 (m, 1H), 5.10 (s, 2H), 3.52-3.63(m, 2H), 2.89 (s, 3H), 0.88-0.95 (m, 2H), 0.00 (s, 9H). ESI [M+H]=228.0

d) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[methyl-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand N-methyl-1-(2-trimethylsilylethoxy-methyl)imidazol-2-amine, usingGeneral Method F. ESI [M+H]=677.3.

e) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[1H-imidazol-2-yl(methyl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 150)

From isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[methyl-[1-(2-trimethylsilyl-ethoxymethyl)imidazol-2-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate,using General Method I. ¹H NMR (400 MHz, methanol-d₄) δ=8.11 (d, J=2.25Hz, 1H), 7.80 (s, 1H), 7.65-7.76 (m, 2H), 7.06 (s, 2H), 4.75 (br s, 1H),3.60 (s, 3H), 3.48 (tt, J=11.58, 3.99 Hz, 1H), 3.05 (tt, J=12.05, 3.52Hz, 1H), 2.90 (q, J=7.25 Hz, 2H), 2.22-2.34 (m, 2H), 2.02-2.15 (m, 2H),1.73 (qd, J=12.84, 3.00 Hz, 2H), 1.37-1.53 (m, 2H), 1.25 (br d, J=6.25Hz, 6H), 1.00-1.08 (m, 3H). ESI [M+H]=547.2.

Example 125 Preparation of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 151)

a) Synthesis of 2-(4H-1,2,4-triazol-3-yl)isoindoline-1,3-dione

A mixture of 1H-1,2,4-triazol-3-amine (8.4 g, 99.9 mmol, 1 eq) andisobenzofuran-1,3-dione (14.80 g, 99.9 mmol, 1 eq) in dioxane (200 mL)the mixture was stirred at 120° C. for 10 h under N₂ atmosphere. Themixture was cooled to 25° C., and then filtered to yield2-(4H-1,2,4-triazol-3-yl)isoindoline-1,3-dione (14 g, 65.3 mmol, 65.4%yield) as a white solid. ESI [M−H]=212.9.

b) Synthesis of2-[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]isoindoline-1,3-dione

To a mixture of 2-(chloromethoxy)ethyl-trimethyl-silane (5.84 g, 35.0mmol, 1.5 eq), 2-(4H-1,2,4-triazol-3-yl)isoindoline-1,3-dione (5 g, 23.3mmol, 1 eq) was added NaH (1.40 g, 35.0 mmol, 60% in oil, 1.5 eq) in DMF(50 mL), and then the mixture was stirred at 50° C. for 5 h under N₂atmosphere. The reaction mixture was quenched with H₂O (20 mL) andextracted with ethyl acetate 180 mL (60 mL×3). The combined organiclayers were washed with sat.aq. NaCl 100 mL (20 mL×5), dried overNa₂SO₄, filtered and concentrated under reduced pressure to yield2-[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]isoindoline-1,3-dione(9 g, crude) as yellow oil. ESI [M+H]=345.2.

c) Synthesis of 4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine

To a solution of2-[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]isoindoline-1,3-dione(8 g, 23.2 mmol, 1 eq) in THF (40 mL) and MeOH (40 mL) was addedNH₂—NH₂.H₂O (1.74 g, 34.8 mmol, 98% purity, 1.5 eq,), and then themixture was stirred at 25° C. for 10 h under N₂ atmosphere. The mixturewas concentrated, and purified by column chromatography (SiO₂, petroleumether:ethyl acetate=1:1 to 0:1) to yield4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-amine (2 g, 9.3 mmol,40% yield) as white solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.11-8.25 (m,1H), 5.25 (br s, 2H), 3.51-3.69 (m, 2H), 0.81-1.00 (m, 2H), −0.10-0.10(m, 9H). ESI [M+H]=215.1.

d) Synthesis of isopropyl trans-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

From isopropyl(trans-4-(5-(4-amino-2-(N-(tert-butyl)sulfamoyl)phenyl)thiazol-2-yl)cyclohexyl)carbamate,using General Method L. ¹H NMR (400 MHz, methanol-d₄) δ=8.26 (d, J=2.2Hz, 1H), 7.83-7.76 (m, 2H), 7.41 (d, J=8.2 Hz, 1H), 4.85-4.78 (m, 1H),3.52-3.39 (m, 1H), 3.03 (tt, J=3.6, 12.0 Hz, 1H), 2.28-2.18 (m, 2H),2.12-2.02 (m, 2H), 1.70 (dq, J=2.6, 12.9 Hz, 2H), 1.46-1.34 (m, 2H),1.22 (br d, J=6.2 Hz, 6H), 1.09 (s, 9H).

e) Synthesis of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

A mixture of isopropyltrans-N-[4-[5-[4-bromo-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(150 mg, 268.5 umol, 1 eq.),4-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-amine (86 mg, 402.8umol, 1.5 eq.), Cs₂CO₃ (175 mg, 537.1 umol, 2 eq.), Brettphos (14 mg,26.8 umol, 0.1 eq.) and Pd₂(dba)₃ (24 mg, 26.8 umol, 0.1 eq.) in t-BuOH(1.5 mL) and toluene (1.5 mL) was stirred at 100° C. for 12 h under Aratmosphere. The reaction mixture was concentrated, and purified byprep-TLC (SiO₂, petroleum ether:ethyl acetate=1:1) to yield isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(205 mg, crude) as a yellow solid. ESI [M+H]=692.3.

f) Synthesis of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 151)

Isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(80 mg, 115.6 umol, 1 eq.) and TsOH.H₂O (32 mg, 173.4 umol, 1.5 eq.)were taken up into a microwave tube with MeOH (3 mL). The sealed tubewas heated at 100° C. for 0.5 h under microwave. The reaction mixturewas concentrated under reduced pressure and purified by prep-HPLC (TFAcondition: column: Nano-micro Kromasil C18 80*25 mm 3 um; mobile phase:[water(0.1% TFA)-ACN]; B %: 24%-58%,7 min) to yield isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(7 mg, 13.3 umol, 12% yield, 100% purity) as a pale yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=9.74 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.30 (br s,1H), 7.68 (dd, J=2.3, 8.5 Hz, 1H), 7.62 (s, 1H), 7.30 (d, J=8.4 Hz, 1H),7.00 (br d, J=7.7 Hz, 1H), 6.79 (s, 1H), 4.72 (td, J=6.2, 12.5 Hz, 1H),3.30 (td, J=3.6, 7.4 Hz, 1H), 2.87 (tt, J=3.4, 11.9 Hz, 1H), 2.11 (br d,J=11.7 Hz, 2H), 1.90 (br d, J=10.4 Hz, 2H), 1.55 (dq, J=2.6, 12.7 Hz,2H), 1.37-1.25 (m, 2H), 1.14 (d, J=6.4 Hz, 6H), 1.07 (s, 9H). ESI[M+H]=562.3.

Example 126 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 152)

a) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[4-(2-trimethyl-silylethoxymethyl)-1,2,4-triazol-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate

A mixture of isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(0.13 g, 245.0 umol, 1 eq.),4-(2-trimethylsilylethoxy-methyl)-1,2,4-triazol-3-amine (105 mg, 490.1umol, 2 eq.), Pd₂(dba)₃ (22 mg, 24.5 umol, 0.1 eq.), Cs₂CO₃ (159 mg,490.1 umol, 2 eq.) anddicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(13 mg, 24.5 umol, 0.1 eq.) in toluene (2 mL) and t-BuOH (2 mL) wasstirred at 100° C. for 12 h under N₂ atmosphere. The reaction mixturewas concentrated under reduced pressure to give a residue which waspurified by prep-TLC (SiO₂, petroleum ether:ethyl acetate=0:1) to yieldisopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[4-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(120 mg, 180.7 umol, 74% yield) as a yellow solid. ESI [M+H]=664.3.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 152)

A mixture of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[4-(2-trimethylsilyl-ethoxymethyl)-1,2,4-triazol-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(95 mg, 143.0 umol, 1 eq.) and TsOH.H₂O (40 mg, 214.6 umol, 1.5 eq.)were taken up into a microwave tube with MeOH (2 mL). The sealed tubewas heated at 100° C. for 0.5 h under microwave. The reaction mixturewas concentrated under reduced pressure to give a residue, which waspurified by prep-HPLC (TFA condition: column: Phenomenex Luna C18 100*30mm*5 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 15%-50%,12 min) toyield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(4H-1,2,4-triazol-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(38 mg, 72.9 umol, 51% yield) as a yellow gum. ¹H NMR (400 MHz, DMSO-d₆)δ=9.94-9.78 (m, 1H), 8.44-8.33 (m, 2H), 7.85-7.80 (m, 1H), 7.75-7.71 (m,1H), 7.45-7.40 (m, 1H), 7.38-7.33 (m, 1H), 7.15-7.06 (m, 1H), 4.84 (td,J=6.2, 12.4 Hz, 1H), 3.45-3.35 (m, 1H), 3.04-2.90 (m, 3H), 2.27-2.19 (m,2H), 2.05-1.97 (m, 2H), 1.71-1.60 (m, 2H), 1.50-1.36 (m, 2H), 1.26 (d,J=6.3 Hz, 6H), 1.12-1.04 (m, 3H). ESI [M+H]=534.3.

Example 127 Preparation of isopropyltrans-[4-[5-[4-(oxazol-2-ylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(153)

a) Synthesis of isopropyltrans-N-[4-[5-(4-bromo-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate

From isopropyl trans-N-[4-[5-(4-amino-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamate, using General Method L. ¹H NMR (400MHz, methanol-d₄) δ=8.23 (d, J=2.00 Hz, 1H), 7.86 (dd, J=8.19, 2.06 Hz,1H), 7.76 (s, 1H), 7.46 (d, J=8.13 Hz, 1H), 4.80-4.86 (m, 1H), 3.47 (tt,J=11.44, 3.63 Hz, 1H), 3.02-3.09 (m, 1H), 2.97 (br t, J=6.63 Hz, 4H),2.19-2.25 (m, 2H), 2.09 (br d, J=10.26 Hz, 2H), 1.77-1.82 (m, 4H),1.64-1.75 (m, 2H), 1.41-1.46 (m, 2H), 1.24 (br d, J=6.00 Hz, 6H). ESI[M+H]=556.1/558.1.

b) Synthesis of isopropyltrans-[4-[5-[4-(oxazol-2-ylamino)-2-pyrrolidin-1-ylsulfonyl-phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 153)

From isopropyltrans-N-[4-[5-(4-bromo-2-pyrrolidin-1-ylsulfonyl-phenyl)thiazol-2-yl]cyclohexyl]carbamateand 2-amino oxazole, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.27 (d, J=2.38 Hz, 1H), 7.68 (dd, J=8.38, 2.38 Hz, 1H),7.58 (s, 1H), 7.41 (d, J=0.88 Hz, 1H), 7.34 (d, J=8.38 Hz, 1H), 6.89 (d,J=0.75 Hz, 1H), 4.72 (br s, 1H), 3.30-3.41 (m, 1H), 3.00 (s, 4H),2.85-2.94 (m, 1H), 2.05-2.16 (m, 2H), 1.92-2.01 (m, 2H), 1.76 (dt,J=6.47, 3.46 Hz, 4H), 1.59 (qd, J=12.86, 2.94 Hz, 2H), 1.31 (qd,J=12.55, 3.13 Hz, 2H), 1.13 (br d, J=6.13 Hz, 6H). ESI [M+H]=560.1.

Example 128 Preparation of isopropyl(trans-4-(5-(2-(N-(tert-butyl)sulfamoyl)-4-(oxazol-2-ylamino)phenyl)thiazol-2-yl)cyclohexyl)carbamate(Compound 42)

Following the same protocol and under the same reaction conditions asfor Compound 153, Compound 42 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.44 (d, J=2.4 Hz, 1H), 7.81 (dd, J=2.5, 8.4 Hz, 1H),7.73 (s, 1H), 7.52 (d, J=1.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 7.00 (d,J=1.0 Hz, 1H), 4.84-4.80 (m, 1H), 3.48 (tt, J=3.8, 11.7 Hz, 1H), 3.02(tt, J=3.5, 12.1 Hz, 1H), 2.29-2.21 (m, 2H), 2.12-2.05 (m, 2H), 1.72(dq, J=3.0, 12.9 Hz, 2H), 1.49-1.38 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H),1.16 (s, 9H). ESI [M+H]=562.2.

Example 129 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-(1H-imidazol-2-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 56)

From isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand 2-bromo-1H-imidazole, using General Method K. ¹H NMR (400 MHz,methanol-d₄) δ=7.90 (d, J=2.4 Hz, 1H), 7.78-7.69 (m, 1H), 7.59-7.44 (m,2H), 7.12 (s, 2H), 4.85-4.76 (m, 1H), 3.52-3.38 (m, 1H), 3.02 (tt,J=3.4, 12.0 Hz, 1H), 2.93-2.80 (m, 2H), 2.34-2.14 (m, 2H), 2.13-2.02 (m,2H), 1.77-1.63 (m, 2H), 1.41 (dq, J=3.1, 12.6 Hz, 2H), 1.22 (br d, J=6.0Hz, 6H), 1.05-0.97 (m, 3H). ESI [M+H]=533.2.

Example 130 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isopropylimidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 154)

a) Synthesis of 2-bromo-1-isopropyl-imidazole

To a mixture of 2-bromo-1H-imidazole (300 mg, 2 mol, 1 eq.), NaH (245mg, 6 mmol, 60% in oil, 3 eq.) in THF (3 mL) was added 2-bromopropane(753 mg, 6 mmol, 3 eq.). The mixture was stirred at 25° C. for 6 h underN₂ atmosphere. The reaction mixture was quenched by H₂O (10 mL) andextracted with EtOAc 60 mL (20 mL×3). The combined organic layers werewashed with sat.aq. NaCl 60 mL (12 mL×5), dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified byprep-HPLC (column: Nano-micro Kromasil C18 100*30 mm 5 um; mobile phase:[water(0.1% TFA)-ACN]; B %: 1%-25%,10 min) to yield2-bromo-1-isopropyl-imidazole (300 mg, 2 mmol, 78% yield) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ=7.36 (d, J=1.76 Hz, 1H), 7.17 (s, 1H), 4.59(spt, J=6.73 Hz, 1H), 1.50 (d, J=6.62 Hz, 6H). ESI [M+H]=188.9/190.9.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-isopropylimidazol-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 154)

From isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclo-hexyl]carbamateand 2-bromo-1-isopropyl-imidazole, using General Method K. ¹H NMR(methanol-d₄, 400 MHz) δ=7.87 (d, 1H, J=2.4 Hz), 7.7-7.8 (m, 1H),7.5-7.6 (m, 1H), 7.4-7.5 (m, 2H), 7.23 (d, 1H, J=2.4 Hz), 4.63 (quin,1H, J=6.8 Hz), 3.45 (br t, 1H, J=11.6 Hz), 3.1-3.2 (m, 1H), 3.0-3.1 (m,1H), 2.8-2.9 (m, 2H), 2.24 (br d, 2H, J=12.6 Hz), 2.0-2.1 (m, 2H),1.6-1.8 (m, 2H), 1.55 (d, 6H, J=6.6 Hz), 1.3-1.5 (m, 2H), 1.22 (br d,6H, J=6.0 Hz), 0.9-1.0 (m, 3H). ESI [M+H]=575.2.

Example 131 Preparation of isopropyltrans-N-[4-[5-[12-(ethylsulfamoyl)-4-[(2-hydroxypyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 156)

a) Synthesis of isopropyltrans-N-[4-[5-[4-[(2-chloropyrimidin-4-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 155)

To a solution of isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(200 mg, 429 umol, 1.0 eq.) in i-PrOH (2 mL) was added2,4-dichloropyrimidine (127 mg, 857 umol, 2.0 eq.) and HCl (12 M, onedrop) and the mixture was stirred at 25° C. for 1 h. The reactionmixture was then concentrated under reduced pressure to yield isopropyltrans-N-[4-[5-[4-[(2-chloropyrimidin-4-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(350 mg, crude) as a yellow oil. 40 mg of crude was purified byprep-HPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase:[water(0.1% TFA)-ACN]; B %: 45%-65%,10 min) to give pure compoundCYT-2056 (2.93 mg, 86.4% purity) as a gray solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.50 (d, J=2.20 Hz, 1H), 8.20 (d, J=5.87 Hz, 1H),7.90-8.00 (m, 1H), 7.77 (s, 1H), 7.48-7.52 (m, 1H), 6.80 (d, J=5.99 Hz,1H), 4.82-4.84 (m, 1H), 3.48 (ddd, J=3.55, 7.83, 11.74 Hz, 1H), 3.03 (q,J=7.30 Hz, 3H), 2.27 (br d, J=12.23 Hz, 2H), 2.05-2.15 (m, 2H), 1.73(dq, J=3.12, 12.82 Hz, 2H), 1.44 (dq, J=3.36, 12.53 Hz, 2H), 1.25 (br d,J=6.11 Hz, 6H), 1.10 (t, J=7.21 Hz, 3H). ESI [M+H]=579.2.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-hydroxypyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 156)

A mixture of isopropyltrans-N-[4-[5-[4-[(2-chloropyrimidin-4-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(250 mg, 432 umol, 1.0 eq.) in formic acid (2.5 mL) was stirred at 70°C. for 12 h. The reaction mixture was concentrated under reducedpressure and then purified by prep-HPLC (column: Phenomenex Luna C18200*40 mm*10 um; mobile phase: [water(0.2% FA)-ACN]; B %: 1%-30%,8 min)to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-hydroxypyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(7 mg, 13 umol, 3% yield, 97% purity) as a white solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.82 (s, 1H), 7.94 (dd, J=2.14, 8.38 Hz, 1H), 7.74 (s,1H), 7.59 (d, J=7.09 Hz, 1H), 7.48 (d, J=8.31 Hz, 1H), 6.09 (d, J=7.09Hz, 1H), 4.76-4.83 (m, 1H), 3.42-3.55 (m, 1H), 2.93-3.08 (m, 3H), 2.26(br d, J=12.23 Hz, 2H), 2.10 (br d, J=10.39 Hz, 2H), 1.65-1.79 (m, 2H),1.37-1.51 (m, 2H), 1.25 (br d, J=6.11 Hz, 6H), 1.13 (t, J=7.21 Hz, 3H).ESI [M+H]=561.2.

Example 132 Preparation of isopropyltrans-N-[4-[5-[4-[(6-ethylpyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 157)

a) Synthesis of 6-vinylpyridazin-3-amine

A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.1 g, 6.9mmol, 1.2 eq.), 6-bromopyridazin-3-amine (1 g, 5.8 mmol, 1.0 eq.),Cs₂CO₃ (5.6 g, 17.3 mmol, 3.0 eq.) and Pd(dppf)Cl₂ (420 mg, 575 umol,0.1 eq.) in dioxane (20 mL)/H₂O (10 mL) was stirred at 80° C. for 3 hunder N₂ atmosphere. The reaction mixture was concentrated under reducedpressure and then purified by column chromatography (SiO₂, petroleumether:ethyl acetate=10:1 to 0:1) to yield 6-vinylpyridazin-3-amine (0.3g, 2.5 mmol, 43% yield) as a pale yellow solid. ESI [M+H]=122.0.

b) Synthesis of 6-ethylpyridazin-3-amine

To a solution of 6-vinylpyridazin-3-amine (0.3 g, 2.5 mmol, 1.0 eq.) andAcOH (15 mg, 248 umol, 0.1 eq.) in EtOAc (20 mL) was added Pd/C (100 mg,10% purity) under N₂.

The suspension was degassed under vacuum and purged with H₂ for 3 timesand then stirred under H₂ (15 psi) at 25° C. for 2 h. The reactionmixture was filtered, the filtrate was concentrated under reducedpressure and then purified by prep-HPLC (column: Phenomenex Gemini-NXC18 75*30 mm*3 um; mobile phase: [water(10 mM NH₄HCO₃)-ACN]; B %:1%-15%,10 min) to yield 6-ethylpyridazin-3-amine (220 mg, 1.8 mmol, 72%yield) as a white solid. ¹H NMR (400 MHz, methanol-d₄) δ=7.30-7.24 (m,1H), 6.96-6.86 (m, 1H), 2.80-2.69 (m, 2H), 1.33-1.19 (m, 3H). ESI[M+H]=124.2.

c) Synthesis of isopropyltrans-N-[4-[5-[4-[(6-ethylpyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 157)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 6-ethylpyridazin-3-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.61-8.53 (m, 1H), 8.11-8.02 (m, 1H), 7.95-7.88 (m, 1H),7.87-7.79 (m, 1H), 7.79-7.74 (m, 1H), 7.56-7.49 (m, 1H), 4.86 (br d,J=6.8 Hz, 1H), 3.53-3.41 (m, 1H), 3.12-3.00 (m, 3H), 2.94-2.84 (m, 2H),2.32-2.19 (m, 2H), 2.15-1.94 (m, 2H), 1.78-1.57 (m, 2H), 1.53-1.37 (m,5H), 1.29-1.18 (m, 6H), 1.09-0.92 (m, 3H). ESI [M+H]=573.2.

Example 133 Preparation of isopropyltrans-N-[4-[5-[4-[(5-ethylpyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 158)

a) Synthesis of 3,6-dichloro-4-ethyl-pyridazine

AgNO₃ (570 mg, 3.4 mmol, 0.1 eq.), propionic acid (3.0 g, 40.3 mmol, 1.2eq.) and TFA (0.1 mL) were added in that order into a solution of3,6-dichloropyridazine (5.0 g, 34.0 mmol, 1.0 eq.) in H₂O (50 mL). Thereaction solution was heated to 70° C., then slowly added (NH₄)₂S₂O₈(15.3 g, 68 mmol, 2.0 eq.). The reaction was stirred at 70° C. for 12 h,then extracted with dichloromethane (90 mL, 30 mL×3), The combinedorganic layers was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=10:1 to 5:1) toyield 3,6-dichloro-4-ethyl-pyridazine (3.1 g, 17.5 mmol, 52% yield) as ayellow oil which was used directly in the next step.

b) Synthesis of6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-ethyl-pyridazin-3-amine

To a solution of 3,6-dichloro-4-ethyl-pyridazine (3.1 g, 17.5 mmol, 1eq.) in n-BuOH (50 mL) was added (2,4-dimethoxyphenyl)methanamine (4.4g, 26.3 mmol, 1.5 eq.) and K₂CO₃ (4.8 g, 35.0 mmol, 2.0 eq.). Themixture was stirred at 100° C. for 12 h, and then concentrated underreduced pressure and purified by column chromatography (SiO₂, petroleumether:ethyl acetate=3:1 to 1:1) to yield6-chloro-N-[(2,4-dimethoxyphenyl) methyl]-5-ethyl-pyridazin-3-amine (700mg, 2 mmol, 13% yield) as a pale yellow oil.

c) Synthesis ofN-[(2,4-dimethoxyphenyl)methyl]-5-ethyl-pyridazin-3-amine

A mixture of6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-ethyl-pyridazin-3-amine (600mg, 2.0 mmol, 1.0 eq.), Pd/C (10 mg, 10% purity), TEA (20 mg, 195 umol,0.1 eq.) and HCOONH₄ (3.7 g, 58.5 mmol, 30 eq.) in EtOH (40 mL) wasstirred at 80° C. for 1 h under N₂ atmosphere. The reaction mixture wasfiltered, and the filtrate was concentrated under reduced pressure toremove solvent. The residue was diluted with H₂O (10 mL), extracted withEtOAc (60 mL, 20 mL×3), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to yieldN-[(2,4-dimethoxy-phenyl)methyl]-5-ethyl-pyridazin-3-amine (700 mg,crude) as a yellow oil. ESI [M+H]=274.1.

d) Synthesis of 5-ethylpyridazin-3-amine

A mixture of N-[(2,4-dimethoxyphenyl)methyl]-5-ethyl-pyridazin-3-amine(600 mg, 2 mmol, 1.0 eq.) in DCM (6 mL)/TFA (2 mL) was stirred at 25° C.for 1 h. The reaction mixture was concentrated under reduced pressureand then purified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*10um; mobile phase: [water(0.1% TFA)-ACN]; B %: 1%-20%,10 min) to yield5-ethylpyridazin-3-amine (250 mg, 2 mmol, 92% yield) as a white solid.¹H NMR (400 MHz, methanol-d₄) δ=8.34 (d, J=1.4 Hz, 1H), 7.26 (s, 1H),2.77 (q, J=7.4 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H). ESI [M+H]=124.0.

e) Synthesis of isopropyltrans-N-[4-[5-[4-[(5-ethylpyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 158)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 5-ethylpyridazin-3-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.94 (s, 1H), 8.52 (d, J=2.4 Hz, 1H), 7.95 (dd, J=2.4,8.4 Hz, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.55 (d, J=8.4 Hz, 1H),4.87-4.82 (m, 1H), 3.48 (tt, J=4.0, 11.6 Hz, 1H), 3.05 (tt, J=3.5, 12.0Hz, 1H), 2.97-2.83 (m, 4H), 2.27 (br d, J=12.3 Hz, 2H), 2.10 (br d,J=10.3 Hz, 2H), 1.73 (dq, J=3.0, 12.8 Hz, 2H), 1.51-1.34 (m, 5H), 1.25(br d, J=6.1 Hz, 6H), 1.05 (t, J=7.2 Hz, 3H). ESI [M+H]=573.2.

Example 134 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-oxo-1H-pyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 160)

a) Synthesis of isopropyltrans-N-[4-[5-[4-[(6-chloropyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 159)

A mixture of isopropyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(500 mg, 1 mmol, 1.0 eq.), 3,6-dichloropyridazine (160 mg, 1 mmol, 1.0eq.) in i-PrOH (5 mL) was stirred at 90° C. for 12 h. The reactionmixture was concentrated under reduced pressure to remove solvent. Theresidue was triturated with EtOAc (10 mL) to yield isopropyltrans-N-[4-[5-[4-[(6-chloropyridazin-3-yl)amino]-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(200 mg, 345 umol, 32% yield) a yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.55 (d, J=2.4 Hz, 1H), 8.04-7.94 (m, 1H), 7.77 (s, 1H),7.56 (d, J=9.5 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.23 (d, J=9.3 Hz, 1H),4.82-4.77 (m, 1H), 3.45 (br t, J=11.7 Hz, 1H), 3.09-3.00 (m, 1H), 2.95(q, J=7.2 Hz, 2H), 2.24 (br d, J=13.5 Hz, 2H), 2.07 (br d, J=11.2 Hz,2H), 1.78-1.60 (m, 2H), 1.48-1.35 (m, 2H), 1.22 (br d, J=6.2 Hz, 6H),1.13-0.99 (m, 3H). ESI [M+H]=579.2.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-oxo-1H-pyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 160)

A mixture of isopropyltrans-N-[4-[5-[4-[(6-chloropyridazin-3-yl)amino]-2-(ethyl-sulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(30 mg, 52 umol, 1 eq.) in AcOH (1 mL) was stirred at 100° C. for 2 hand then concentrated under reduced pressure to remove AcOH. The residuewas purified by SFC (column: (s,s) WHELK-O1 (250 mm*30 mm, 5 um); mobilephase: [0.1% NH₃H₂O IPA]; B %: 50%-50%, min), then by prep-HPLC (column:Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water(0.1% TFA)-ACN];B %: 30%-60%,10 min) to yield isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-oxo-1H-pyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(1 mg, 2 umol, 3% yield, 97% purity) as a pale yellow solid. ¹H NMR (400MHz, methanol-d₄) δ=8.38 (d, J=2.4 Hz, 1H), 7.82 (dd, J=2.5, 8.5 Hz,1H), 7.72-7.65 (m, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.28 (d, J=9.7 Hz, 1H),6.95 (d, J=9.9 Hz, 1H), 4.83-4.73 (m, 1H), 3.45 (br t, J=11.6 Hz, 1H),3.05-2.94 (m, 1H), 2.89 (q, J=7.4 Hz, 2H), 2.23 (br d, J=13.2 Hz, 2H),2.07 (br d, J=10.6 Hz, 2H), 1.76-1.62 (m, 2H), 1.47-1.35 (m, 2H),1.29-1.20 (m, 6H), 1.06-0.98 (m, 3H). ESI [M+H]=561.2.

Example 135 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-methylpyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 161)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 5-methylpyridazin-3-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.86 (br s, 1H), 8.46 (d, J=2.2 Hz, 1H), 7.89 (dd, J=2.2,8.4 Hz, 1H), 7.76 (s, 1H), 7.59-7.49 (m, 2H), 4.84-4.78 (m, 1H), 3.45(tt, J=3.9, 11.6 Hz, 1H), 3.03 (tt, J=3.3, 12.0 Hz, 1H), 2.89 (q, J=7.3Hz, 2H), 2.51 (s, 3H), 2.29-2.19 (m, 2H), 2.13-2.03 (m, 2H), 1.70 (dq,J=3.0, 12.8 Hz, 2H), 1.47-1.33 (m, 2H), 1.22 (br d, J=6.0 Hz, 6H), 1.02(t, J=7.3 Hz, 3H). ESI [M+H]=559.3.

Example 136 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-methylpyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 162)

Following the same protocol and under the same reaction conditions asfor Compound 161, Compound 162 was prepared. ¹H NMR (400 MHz, DMSO-d₆)δ=10.08 (br s, 1H), 8.40 (d, J=2.3 Hz, 1H), 8.00 (dd, J=2.3, 8.5 Hz,1H), 7.75-7.65 (m, 2H), 7.52-7.29 (m, 3H), 7.02 (br d, J=8.6 Hz, 1H),3.34-3.30 (m, 1H), 3.34-3.30 (m, 1H), 2.99-2.78 (m, 3H), 2.58 (s, 3H),2.60-2.56 (m, 2H), 2.22-2.10 (m, 2H), 1.67-1.50 (m, 2H), 1.45-1.27 (m,2H), 1.17 (d, J=6.3 Hz, 6H), 0.97 (t, J=7.2 Hz, 3H). ESI [M+H]=559.2.

Example 137 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropylpyrazin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 163)

a) Synthesis of 5-isopropenylpyrazin-2-amine

A mixture of 5-bromopyrazin-2-amine (1.0 g, 5.8 mmol, 1.0 eq.),2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7.5 mmol,1.3 eq.), Cs₂CO₃ (5.6 g, 17.2 mmol, 3.0 eq.) and Pd(dppf)Cl₂ (421 mg,575 umol, 0.1 eq.) in dioxane (20 mL)/H₂O (10 mL) was stirred at 80° C.for 12 h under N₂ atmosphere. The reaction mixture was concentratedunder reduced pressure to remove solvent, then the residue was dilutedwith H₂O (10 mL) and extracted with EtOAc (90 mL, 30 mL×3). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=10:1 to 5:1 to 1:1 to 0:1) to yield5-isopropenylpyrazin-2-amine (750 mg, 97% yield) as a white solid. ¹HNMR (400 MHz, methanol-d₄) δ=8.06 (s, 1H), 7.90 (d, J=1.10 Hz, 1H), 5.63(d, J=0.66 Hz, 1H), 5.00-5.13 (m, 1H), 2.11 (s, 3H). ESI [M+H]=136.1.

b) Synthesis of 5-isopropylpyrazin-2-amine

To a solution of 5-isopropenylpyrazin-2-amine (490 mg, 4 mmol, 1.0 eq.)in EtOAc (20 mL) was added AcOH (22 mg, 363 umol, 0.1 eq.) and Pd/C (100mg, 10% purity). The suspension was degassed under vacuum and purgedwith H₂ for 3 times. The mixture was stirred under H₂ (15 psi) at 25° C.for 4 h, then filtered and concentrated under reduced pressure to yield5-isopropylpyrazin-2-amine (500 mg, crude) as a pale yellow oil. ¹H NMR(400 MHz, methanol-d₄) δ=7.87 (d, J=1.32 Hz, 1H), 7.78 (d, J=1.10 Hz,1H), 2.91 (dt, J=13.89, 6.95 Hz, 1H), 1.23 (d, J=7.06 Hz, 6H). ESI[M+H]=138.1.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropylpyrazin-2-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 163)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 5-isopropylpyrazin-2-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=8.58 (d, J=2.38 Hz, 1H), 8.16 (dd, J=8.88, 1.25 Hz, 2H),7.94 (dd, J=8.38, 2.38 Hz, 1H), 7.74 (s, 1H), 7.42 (d, J=8.38 Hz, 1H),4.78-4.86 (m, 1H), 3.43-3.52 (m, 1H), 3.00-3.10 (m, 2H), 2.97 (q, J=7.21Hz, 2H), 2.22-2.30 (m, 2H), 2.06-2.14 (m, 2H), 1.72 (qd, J=12.84, 3.00Hz, 2H), 1.43 (qd, J=12.57, 3.31 Hz, 2H), 1.33 (d, J=6.88 Hz, 6H), 1.25(br d, J=6.13 Hz, 6H), 1.09 (t, J=7.25 Hz, 3H). ESI [M+H]=587.2.

Example 138 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropylpyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 164)

a) Synthesis of 3,6-dichloro-4-isopropyl-pyridazine

AgNO₃ (57 mg, 336 umol, 0.1 eq.), 2-methylpropanoic acid (355 mg, 4mmol, 1.2 eq.) and TFA (0.1 mL) were added (in order) to a solution of3,6-dichloropyridazine (500 mg, 3 mmol, 1.0 eq.) in H₂O (5 mL). Thereaction solution was heated to 70° C., then slowly added (NH₄)₂S₂O₈(1.5 g, 6.7 mmol, 2.0 eq.). The reaction was stirred for 12 h at 70° C.,then extracted with dichloromethane (90 mL, 30 mL×3). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduced pressure to yield 3,6-dichloro-4-isopropyl-pyridazine (650 mg,crude) as a yellow oil. ESI [M+H]=191.0/193.0.

b) Synthesis of6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isopropyl-pyridazin-3-amine

To a solution of (2,4)-dimethoxyphenyl)methanamine (853 mg, 4.5 mmol,1.5 eq.) and 3,6-dichloro-4-isopropyl-pyridazine (650 mg, 3 mmol, 1.0eq.) in n-BuOH (30 mL) was added K₂CO₃ (1.4 g, 10.2 mmol, 3.0 eq.) andthe mixture was stirred at 100° C. for 12 h. The reaction mixture wasconcentrated and purified by column chromatography (SiO₂, petroleumether:ethyl acetate=10:1 to 0:1) to yield6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isopropyl-pyridazin-3-amine(320 mg, 994 umol, 29% yield) as a light yellow oil which was useddirectly in the next step.

c) Synthesis ofN-[(2,4-dimethoxyphenyl)methyl]-5-isopropyl-pyridazin-3-amine

To a solution of6-chloro-N-[(2,4-dimethoxyphenyl)methyl]-5-isopropyl-pyridazin-3-amine(300 mg, 932 umol, 1.0 eq.) and Pd/C (300 mg, 10% purity) in EtOH (10mL) was added TEA (573 mg, 6 mmol, 6.0 eq.) and HCOONH₄ (1.8 g, 28.0mmol, 30.0 eq.). The mixture was stirred at 80° C. for 1 h, thenfiltered and concentrated. The residue was diluted with H₂O (10 mL) andextracted with EtOAc (45 mL, 15 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure toyield N-[(2,4-dimethoxyphenyl)methyl]-5-isopropyl-pyridazin-3-amine (250mg, crude) as a yellow oil. ESI [M+H]=287.9.

d) Synthesis of 5-isopropylpyridazin-3-amine

A solution ofN-[(2,4-dimethoxyphenyl)methyl]-5-isopropyl-pyridazin-3-amine (230 mg,800 umol, 1.0 eq.) in DCM (20 mL) and TFA (7 mL) was stirred at 25° C.for 1 h. The mixture was concentrated, diluted with H₂O (20 mL) andextracted with EtOAc (60 mL, 20 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by prep-HPLC (column:Nano-micro Kromasil C18 100*40 mm 10 um; mobile phase: [water(10 mMNH₄HCO₃)-ACN]; B %: 1%-20%,8 min) to yield 5-isopropylpyridazin-3-amine(30 mg, 218 umol, 27% yield) as a white solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.42 (s, 1H), 7.25 (s, 1H), 3.04 (spt, J=6.9 Hz, 1H),1.33 (d, J=6.8 Hz, 6H). ESI [M+H]=138.0.

e) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(5-isopropylpyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 164)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 5-isopropylpyridazin-3-amine, using General Method F. ¹H NMR (400MHz, DMSO-d₆) δ=9.90 (s, 1H), 8.84 (s, 1H), 8.40 (d, J=2.1 Hz, 1H), 8.07(dd, J=2.1, 8.4 Hz, 1H), 7.69 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.39 (t,J=5.5 Hz, 1H), 7.11 (s, 1H), 7.02 (br d, J=7.3 Hz, 1H), 4.75 (td, J=6.2,12.5 Hz, 1H), 3.32 (br s, 1H), 3.00-2.90 (m, 2H), 2.89-2.80 (m, 2H),2.16 (br d, J=11.6 Hz, 2H), 1.93 (br d, J=10.0 Hz, 2H), 1.67-1.53 (m,2H), 1.42-1.29 (m, 2H), 1.26 (d, J=6.9 Hz, 6H), 1.18 (d, J=6.3 Hz, 6H),0.99 (t, J=7.2 Hz, 3H). ESI [M+H]=587.3.

Example 139 Preparation of methyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-methyl-oxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 165)

a) Synthesis of methyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

To a solution of methyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(2.5 g, 5.7 mmol, 1.0 eq.) in MeCN (50 mL) was added CuBr (981 mg, 7mmol, 1.2 eq.),[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (4.0 g,17.1 mmol, 3.0 eq.), TBAB (11.0 g, 34.2 mmol, 6.0 eq.) and NaNO₂ (1.2 g,17.1 mmol, 3 eq.). The reaction mixture was stirred at 25° C. for 1 h,then quenched with with Na₂CO₃ sat.aq. (50 mL), and concentrated underreduced pressure to remove MeCN.

The residue was diluted with H₂O (50 mL) and extracted with EtOAc (300mL, 100 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by reversed-phase HPLC(0.1%TFA condition) to yield methyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(1.4 g, 2.8 mmol, 48.9% yield) as a yellow solid. ¹H NMR (400 MHz,methanol-d₄) δ=8.21 (d, J=1.6 Hz, 1H), 7.93-7.71 (m, 2H), 7.43 (d, J=8.1Hz, 1H), 3.65 (s, 3H), 3.48 (br t, J=11.6 Hz, 1H), 3.04 (br s, 1H), 2.89(q, J=7.1 Hz, 2H), 2.26 (br d, J=12.5 Hz, 2H), 2.09 (br d, J=11.0 Hz,2H), 1.72 (q, J=11.9 Hz, 2H), 1.51-1.37 (m, 2H), 1.04 (t, J=7.2 Hz, 3H).ESI [M+H]=502.1/504.1.

b) Synthesis of methyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(3-methyl-oxetan-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 165)

From methyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 3-methyloxetan-3-amine, using General Method F. ¹H NMR (400 MHz,methanol-d₄) δ=7.60 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.11 (d, J=2.4 Hz,1H), 6.60 (dd, J=2.5, 8.3 Hz, 1H), 4.79 (d, J=6.2 Hz, 2H), 4.59 (d,J=6.0 Hz, 2H), 3.62 (s, 3H), 3.50-3.39 (m, 1H), 3.03-2.92 (m, 1H), 2.85(q, J=7.1 Hz, 2H), 2.21 (br d, J=12.8 Hz, 2H), 2.06 (br d, J=10.8 Hz,2H), 1.74-1.60 (m, 5H), 1.40 (dq, J=3.1, 12.5 Hz, 2H), 1.01 (t, J=7.3Hz, 3H). ESI [M+H]=509.2.

Example 140 Preparation of methyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-pyrazol-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 166)

Following the same protocol and under the same reaction conditions asfor Compound 165, Compound 166 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.71 (s, 1H), 7.64 (s, 2H), 7.47 (d, J=2.4 Hz, 1H), 7.27(d, J=8.4 Hz, 1H), 7.00 (dd, J=2.5, 8.4 Hz, 1H), 3.65 (s, 3H), 3.48(ddd, J=4.0, 7.5, 11.5 Hz, 1H), 3.10-2.99 (m, 1H), 2.88 (q, J=7.3 Hz,2H), 2.25 (br d, J=13.0 Hz, 2H), 2.09 (br d, J=10.5 Hz, 2H), 1.78-1.65(m, 2H), 1.50-1.37 (m, 2H), 1.03 (t, J=7.3 Hz, 3H). ESI [M+H]=505.2.

Example 141 Preparation of methyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1H-pyrazol-5-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 167)

Following the same protocol and under the same reaction conditions asfor Compound 165, Compound 167 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=8.00 (d, J=1.5 Hz, 1H), 7.87 (s, 1H), 7.75-7.62 (m, 1H),7.52-7.42 (m, 1H), 7.36 (d, J=8.3 Hz, 1H), 6.11 (br s, 1H), 3.65 (s,3H), 3.56-3.42 (m, 1H), 3.13 (br t, J=11.8 Hz, 1H), 2.95 (q, J=7.2 Hz,2H), 2.27 (br d, J=12.3 Hz, 2H), 2.10 (br d, J=10.8 Hz, 2H), 1.82-1.65(m, 2H), 1.54-1.36 (m, 2H), 1.07 (t, J=7.2 Hz, 3H). ESI [M+H]=505.2.

Example 142 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[(3R)-1-isobutyl-2-oxo-azetidin-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 168)

a) Synthesis of benzylN-[(1R)-1-(hydroxymethyl)-2-(4-methoxyanilino)-2-oxo-ethyl]carbamate

To a solution of 4-methoxyaniline (25.7 g, 208.7 mmol, 1.0 eq.) in THF(300 mL) and DCM (100 mL) was added(2R)-2-(benzyloxycarbonylamino)-3-hydroxy-propanoic acid (10.0 g, 41.7mmol, 0.2 eq.) and EDCI (8.0 g, 41.7 mmol, 0.2 eq.) at 0° C. for 30 min.The mixture was stirred at 25° C. for 12 h and concentrated underreduced pressure. The residue was purified by column chromatography(SiO₂, petroleum ether:ethyl acetate=10:1 to 0:1) to yield benzylN-[(1R)-1-(hydroxymethyl)-2-(4-methoxy-anilino)-2-oxo-ethyl]carbamate(8.0 g, 23.2 mmol, 11% yield) as a white solid. ¹H NMR (400 MHz,methanol-d₄) δ=6.73 (d, J=1.1 Hz, 9H), 4.86-4.84 (m, 2H), 4.39-4.31 (m,1H), 3.86 (br d, J=5.4 Hz, 2H), 3.80-3.75 (m, 3H). ESI [M+H]=345.0.

b) Synthesis of benzylN-[(3R)-1-(4-methoxyphenyl)-2-oxo-azetidin-3-yl]carbamate

To a solution of benzylN-[(1R)-1-(hydroxymethyl)-2-(4-methoxyanilino)-2-oxo-ethyl]carbamate(7.0 g, 20.3 mmol, 1.0 eq.) in DMF (200 mL) was added1-imidazol-1-ylsulfonylimidazole (6.0 g, 30.5 mmol, 1.5 eq.) at 0° C.under under N₂ atmosphere. The resulting mixture was stirred at 0° C.for additional 0.5 h and then cooled to −20° C. Under vigorous stirring,NaH (1.2 g, 30.5 mmol, 60% purity, 1.5 eq.) was added portionwise. Theresulting suspension was vigorously stirred at −20° C. for additional 1h. The reaction mixture was quenched with water (200 mL). The collectedprecipitate was filtered, washed with additional water (100 mL) and thendried under reduced pressure to yield benzylN-[(3R)-1-(4-methoxyphenyl)-2-oxo-azetidin-3-yl]carbamate (4.5 g, 13.8mmol, 68% yield) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃)δ=7.32-7.08 (m, 7H), 6.83-6.72 (m, 2H), 5.70-5.60 (m, 1H), 5.10-5.01 (m,2H), 4.96-4.87 (m, 1H), 3.89-3.78 (m, 1H), 3.70 (s, 3H), 3.53-3.43 (m,1H). ESI [M+H]=327.1.

c) Synthesis of benzyl N-[(3R)-2-oxoazetidin-3-yl]carbamate

To a solution of benzylN-[(3R)-1-(4-methoxyphenyl)-2-oxo-azetidin-3-yl]carbamate (2.3 g, 7.1mmol, 1.0 eq.) in MeCN (110 mL)/H₂O (88 mL) was added CAN (11.6 g, 21.0mmol, 3.0 eq.) at 0° C. The reaction mixture was stirred at 0° C. for 15min, then quenched by addition of sat.aq. NaHCO₃ (110 mL) at 0° C. Themixture was filtered, and the filtrate was extracted with EtOAc (120 mL,40 mL×3). The combined organic layers dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobilephase:[water(0.1% TFA)-ACN]; B %: 10%-40%,10 min) to yield benzylN-[(3R)-2-oxoazetidin-3-yl]carbamate (890 mg, 4 mmol, 57% yield) as apurple solid. ¹H NMR (400 MHz, CDCl₃) δ=7.45-7.33 (m, 5H), 6.08-5.93 (m,1H), 5.68-5.52 (m, 1H), 5.25-5.08 (m, 2H), 4.97-4.82 (m, 1H), 3.76-3.57(m, 1H), 3.46-3.34 (m, 1H). ESI [M+H]=221.1.

d) Synthesis of (3R)-3-aminoazetidin-2-one

To a solution of benzyl N-[(3R)-2-oxoazetidin-3-yl]carbamate (890 mg, 4mmol, 1 eq.) in THF (50 mL) was added Pd(OH)₂ (50 mg, 10% purity) andPd/C (50 mg, 10% purity). The suspension was stirred under H₂ (50 psi)at 50° C. for 4 h, then filtered and concentrated under reduced pressureto yield (3R)-3-aminoazetidin-2-one (500 mg, crude) as a purple oil. ESI[2M+H]=173.1.

e) Synthesis of (3R)-3-(dibenzylamino)azetidin-2-one

To a solution of (3R)-3-aminoazetidin-2-one (500 mg, 6 mmol, 1.0 eq.),benzaldehyde (555 mg, 5 mmol, 0.9 eq.) in MeOH (20 mL) was added AcOH(34 mg, 580 umol, 0.1 eq.) and NaBH₃CN (1.1 g, 17.4 mmol, 3 eq.). Themixture was stirred at 25° C. for 12 h and then quenched with NH₃.H₂O (5mL). The mixture was concentrated under reduced pressure and thenpurified by column chromatography (SiO₂, Petroleum ether:Ethylacetate=10:1 to 1:1) to yield (3R)-3-(dibenzylamino)azetidin-2-one (620mg, crude) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ=7.44-7.29 (m,10H), 6.58-6.42 (m, 1H), 4.44-4.31 (m, 2H), 4.26 (br d, J=2.5 Hz, 1H),4.11 (br d, J=13.1 Hz, 2H), 3.28 (br d, J=5.4 Hz, 1H), 3.11-3.04 (m,1H). ESI [M+H]=267.1.

Synthesis of (R)-3-(dibenzylamino)-1-isobutylazetidin-2-one

To a solution of (3R)-3-(dibenzylamino)azetidin-2-one (600 mg, 2 mmol, 1eq.) in DMF (2 mL) was added NaH (135 mg, 3 mmol, 60% in oil, 1.5 eq.)and 1-bromo-2-methyl-propane (926 mg, 7 mmol, 3 eq.). The mixture wasstirred at 25° C. for 1 h and then quenched with NH₄Cl (10 mL) at 0° C.The mixture was diluted with H₂O (20 mL) and extracted with EtOAc (60mL, 20 mL×3). The combined organic layers were washed with brine (30mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC (column: Nano-microKromasil C18 100*40 mm 10 um; mobile phase: [water(0.1% TFA)-ACN]; B %:40%-67%,8 min) to yield (R)-3-(dibenzylamino)-1-isobutylazetidin-2-one(220 mg, 682 umol, 30% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃)δ=7.53-7.23 (m, 10H), 4.54-4.37 (m, 2H), 4.34-4.21 (m, 1H), 4.13 (br d,J=13.0 Hz, 2H), 3.39-3.32 (m, 1H), 3.12-3.02 (m, 1H), 2.99-2.87 (m, 2H),1.79-1.68 (m, 1H), 0.90-0.76 (m, 6H). ESI [M+H]=323.1.

g) Synthesis of (3R)-3-amino-1-isobutyl-azetidin-2-one

To a solution of (R)-3-(dibenzylamino)-1-isobutylazetidin-2-one (220 mg,682 umol, 1 eq.) in THF (50 mL) and i-PrOH (50 mL) was added Pd(OH)₂ (20mg, 10%) and Pd/C (20 mg, 10%). The suspension was stirred under H₂ (50psi) at 50° C. for 12 h. The reaction mixture was filtered andconcentrated under reduced pressure to yield(3R)-3-amino-1-isobutyl-azetidin-2-one (210 mg, crude) as a black gum.ESI [2M+H]=285.2.

h) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[(3R)-1-iso-butyl-2-oxo-azetidin-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 168)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand (3R)-3-amino-1-isobutyl-azetidin-2-one, using General Method F. ¹HNMR (400 MHz, methanol-d₄) δ=7.75-7.63 (m, 1H), 7.44-7.36 (m, 1H),7.33-7.23 (m, 1H), 6.98-6.87 (m, 1H), 4.91-4.87 (m, 1H), 3.81-3.75 (m,1H), 3.53-3.42 (m, 1H), 3.38-3.36 (m, 1H), 3.29 (dd, J=2.0, 5.7 Hz, 1H),3.18-3.08 (m, 2H), 3.07-2.96 (m, 1H), 2.94-2.83 (m, 2H), 2.25 (br d,J=12.5 Hz, 2H), 2.14-2.05 (m, 2H), 2.01-1.90 (m, 1H), 1.79-1.60 (m, 2H),1.49-1.36 (m, 2H), 1.25 (br d, J=6.1 Hz, 6H), 1.04 (t, J=7.2 Hz, 3H),0.99 (dd, J=3.8, 6.7 Hz, 6H). ESI [M+H]=592.2.

Example 143 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[[(3S)-1-isobutyl-2-oxo-azetidin-3-yl]amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 169)

Following the same protocol and under the same reaction conditions asfor Compound 168, Compound 169 was prepared. ¹H NMR (400 MHz,methanol-d₄) δ=7.66 (s, 1H), 7.39 (d, J=2.5 Hz, 1H), 7.26 (d, J=8.4 Hz,1H), 6.93 (dd, J=2.4, 8.4 Hz, 1H), 4.81 (br s, 1H), 3.79 (t, J=5.2 Hz,1H), 3.52-3.42 (m, 1H), 3.37 (br s, 1H), 3.29 (dd, J=2.0, 5.6 Hz, 1H),3.18-3.07 (m, 2H), 3.07-2.97 (m, 1H), 2.89 (q, J=7.2 Hz, 2H), 2.25 (brd, J=12.3 Hz, 2H), 2.09 (br d, J=10.3 Hz, 2H), 2.01-1.91 (m, 1H),1.76-1.63 (m, 2H), 1.48-1.37 (m, 2H), 1.25 (br d, J=6.0 Hz, 6H),1.08-0.96 (m, 9H). ESI [M+H]=592.3.

Example 144 Preparation of tert-butyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-isopropylpyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 170)

a) Synthesis of tert-butyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

A mixture of5-amino-N-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide(2.8 g, 8.5 mmol, 1.4 eq), tert-butyltrans-N-[4-(5-bromo-thiazol-2-yl)cyclohexyl]carbamate (2.2 g, 6.1 mmol,1 eq), KF (530 mg, 9 mmol, 1.5 eq), Na₂CO₃ (1.9 g, 18.3 mmol, 3 eq) andPd(PPh₃)₄ (703 mg, 609 umol, 0.1 eq) in toluene (30 mL), EtOH (30 mL)and H₂O (10 mL) was stirred at 80° C. for 2 h under N₂ atmosphere. Thereaction mixture was concentrated under reduced pressure, then dilutedwith H₂O (20 mL) and extracted with EtOAc (90 mL, 30 mL×3), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue which was purified by reversed-phase HPLC (0.1% TFA condition)to yield tert-butyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(2.9 g, 6.0 mmol, 99% yield) as a brown solid. ¹H NMR (400 MHz,methanol-d₄) δ=7.64 (s, 1H), 7.60 (br s, 1H), 7.56 (d, J=3.0 Hz, 1H),7.47 (d, J=3.4 Hz, 1H), 3.46-3.39 (m, 1H), 3.37 (s, 2H), 3.02 (tt,J=3.5, 12.1 Hz, 1H), 2.19 (br d, J=13.5 Hz, 2H), 2.05 (br d, J=10.1 Hz,2H), 1.66 (dt, J=10.1, 12.9 Hz, 2H), 1.46 (s, 9H), 1.45-1.34 (m, 3H),1.23-0.89 (m, 2H). ESI [M+H]=481.2.

b) Synthesis of tert-butyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate

To a solution of tert-butyltrans-N-[4-[5-[4-amino-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(1.0 g, 2.1 mmol, 1.0 eq.) in MeCN (30 mL) was added TBAB (4.0 g, 12.5mmol, 6.0 eq.), CuBr (358 mg, 2.5 mmol, 1.2 eq.),[(1S,4R)-7,7-dimethyl-2-oxo-norbornan-1-yl]methanesulfonic acid (1.5 g,6.0 mmol, 3.0 eq.) and NaNO₂ (430 mg, 6 mmol, 3 eq.). The mixture wasstirred at 25° C. for 1 h, then quenched with sat.aq.Na₂CO₃ (20 mL). Themixture was concentrated, diluted with H₂O (20 mL) and extracted withEtOAc (150 mL, 50 mL×3), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue which was purified by columnchromatography (SiO₂, petroleum ether:ethyl acetate=3:1 to 1:1) to yieldtert-butyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(500 mg, 918 umol, 44% yield) as a yellow oil. ¹H NMR (400 MHz,methanol-d₄) δ=8.18 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2.0, 8.2 Hz, 1H),7.74 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 3.39 (br t, J=11.7 Hz, 1H), 2.99(tt, J=3.5, 12.0 Hz, 1H), 2.85 (q, J=7.3 Hz, 2H), 2.23 (br d, J=12.8 Hz,2H), 2.10-1.99 (m, 2H), 1.75-1.58 (m, 2H), 1.44 (s, 9H), 1.41-1.32 (m,2H), 1.01 (t, J=7.3 Hz, 3H). ESI [M+H]=544.0/546.0.

c) Synthesis of tert-butyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(2-isopropyl-pyrazol-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 170)

From tert-butyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 3-amino-2-isopropylpyrazole, using General Method F. ¹H NMR (400MHz, methanol-d₄) δ=7.77 (s, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.50 (d, J=2.5Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.05 (dd, J=2.5, 8.4 Hz, 1H), 6.19 (d,J=2.0 Hz, 1H), 4.63 (spt, J=6.6 Hz, 1H), 3.42 (br t, J=11.4 Hz, 1H),3.12-3.01 (m, 1H), 2.87 (q, J=7.2 Hz, 2H), 2.26 (br d, J=12.9 Hz, 2H),2.08 (br d, J=10.5 Hz, 2H), 1.79-1.65 (m, 2H), 1.48-1.44 (m, 15H),1.44-1.35 (m, 2H), 1.02 (t, J=7.3 Hz, 3H). ESI [M+H]=589.3.

Example 145 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropylpyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 171)

a) Synthesis of 6-isopropenylpyrimidin-4-amine

A mixture of 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2g, 7.1 mmol, 1.3 eq.), 6-bromopyrimidin-4-amine (950 mg, 5 mmol, 1 eq.),Cs₂CO₃ (5.3 g, 16.4 mmol, 3 eq.) and Pd(dppf)Cl₂ (399 mg, 546 umol, 0.1eq.) in H₂O (15 mL)/dioxane (30 mL) was stirred at 90° C. for 12 h underN₂ atmosphere. The reaction mixture was concentrated under reducedpressure to remove solvent. The residue was diluted with H₂O (20 mL) andextracted with EtOAc (60 mL, 20 mL×3). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue which was purified by column chromatography (SiO₂,petroleum ether:ethyl acetate=1:0 to 0:1) to yield6-isopropenylpyrimidin-4-amine (330 mg, 2 mmol, 45% yield) as a paleyellow solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.19 (d, J=0.9 Hz, 1H),6.51 (d, J=1.0 Hz, 1H), 5.84 (d, J=0.8 Hz, 1H), 5.25 (t, J=1.5 Hz, 1H),2.00 (s, 3H). ESI [M+H]=136.0.

b) Synthesis of 6-isopropylpyrimidin-4-amine

To a solution of 6-isopropenylpyrimidin-4-amine (330 mg, 2 mmol, 1 eq.)in EtOAc (20 mL) was added Pd/C (50 mg, 10% purity) and the suspensionwas stirred under H₂ (15 psi) at 25° C. for 2 h. The reaction mixturewas filtered, and the filtrate was concentrated under reduced pressureto yield 6-isopropylpyrimidin-4-amine (320 mg, 2 mmol, 96% yield) as awhite solid. ¹H NMR (400 MHz, methanol-d₄) δ=8.15 (d, J=0.8 Hz, 1H),6.31 (d, J=0.6 Hz, 1H), 2.67 (td, J=6.9, 13.9 Hz, 1H), 1.13 (d, J=7.0Hz, 6H). ESI [M+H]=138.0.

c) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(6-isopropylpyrimidin-4-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 171)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 6-isopropylpyrimidin-4-amine, using General Method F. ¹H NMR (400MHz, methanol-d₄) δ=8.82 (s, 1H), 8.52 (d, J=2.2 Hz, 1H), 7.97 (dd,J=2.2, 8.4 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.91 (s, 1H),4.83-4.77 (m, 1H), 3.50-3.39 (m, 1H), 3.12-2.96 (m, 2H), 2.89 (q, J=7.2Hz, 2H), 2.31-2.16 (m, 2H), 2.13-2.00 (m, 2H), 1.76-1.63 (m, 2H), 1.38(d, J=6.8 Hz, 8H), 1.22 (br d, J=6.2 Hz, 6H), 1.02 (t, J=7.3 Hz, 3H).ESI [M+H]=587.3.

Example 146 Preparation of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-methyl-6-oxo-pyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 172)

a) Synthesis of 6-imino-2-methyl-1H-pyridazin-3-one

To a solution of 6-imino-1,2-dihydropyridazin-3-one (250 mg, 2 mmol, 1eq.) in EtOH (5 mL) was added NaOH (180 mg, 5 mmol, 2 eq.) and MeI (351mg, 2 mmol, 1 eq.). The mixture was stirred at 80° C. for 2 h and thenquenched with NH₃.H₂O (0.1 mL) at 25° C. The mixture was purified byprep-TLC (SiO₂, dichloromethane:methanol=8:1) and further purified byprep-HPLC (column: Waters Xbridge BEH C18 100*25 mm*5 um; mobile phase:[water(10 mM NH₄HCO₃)-ACN]; B %: 1%-12%,10 min) to yield6-imino-2-methyl-1H-pyridazin-3-one (120 mg, 959 umol, 43% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ=6.91 (d, J=9.7 Hz, 1H), 6.71(d, J=9.5 Hz, 1H), 5.73 (s, 2H), 3.39 (s, 3H). ESI [2M+H]=251.1.

b) Synthesis of isopropyltrans-N-[4-[5-[2-(ethylsulfamoyl)-4-[(1-methyl-6-oxo-pyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 172)

From isopropyltrans-N-[4-[5-[4-bromo-2-(ethylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamateand 6-imino-2-methyl-1H-pyridazin-3-one, using General Method F. ¹H NMR(400 MHz, methanol-d₄) δ=8.47 (d, J=2.4 Hz, 1H), 7.80 (dd, J=2.3, 8.3Hz, 1H), 7.72 (s, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.24 (d, J=9.7 Hz, 1H),6.95 (d, J=9.7 Hz, 1H), 4.82-4.77 (m, 1H), 3.74 (s, 3H), 3.54-3.38 (m,1H), 3.09-2.97 (m, 1H), 2.95-2.84 (m, 2H), 2.30-2.18 (m, 2H), 2.11-2.01(m, 2H), 1.77-1.62 (m, 2H), 1.49-1.34 (m, 2H), 1.22 (br d, J=6.2 Hz,6H), 1.03 (t, J=7.2 Hz, 3H). ESI [M+H]=575.3.

Example 147 Preparation of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(6-chloropyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclohexyl]carbamate (Compound173)

To a solution of isopropyltrans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(20 mg, 40 umol, 1 eq) in i-PrOH (2 mL) was added 3,6-dichloropyridazine(18 mg, 121 umol, 3 eq) and the mixture was stirred at 90° C. for 1 h.The reaction mixture was concentrated under reduced pressure andpurified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 um; mobilephase: [water(0.04% HCl)-ACN]; B %: 50%-80%,10 min) to yield isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-[(6-chloropyridazin-3-yl)amino]phenyl]thiazol-2-yl]cyclo-hexyl]carbamate(14 mg, 23 umol, 57% yield, 96% purity) as a white solid. ¹H NMR (400MHz, methanol-d₄) δ=8.65-8.54 (m, 1H), 8.12-8.03 (m, 1H), 7.89-7.81 (m,1H), 7.60-7.54 (m, 1H), 7.50-7.43 (m, 1H), 7.27-7.18 (m, 1H), 4.84-4.80(m, 1H), 3.53-3.41 (m, 1H), 3.15-3.05 (m, 1H), 2.30-2.22 (m, 2H),2.14-2.04 (m, 2H), 1.80-1.65 (m, 2H), 1.50-1.35 (m, 2H), 1.22 (br d,J=6.2 Hz, 6H), 1.17-1.15 (m, 9H). ESI [M+H]=607.2/609.2.

Example 148 Preparation of isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(pyridazin-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(Compound 174)

A mixture of 3-bromopyridazine (13 mg, 81 umol, 2 eq), isopropyltrans-N-[4-[5-[4-amino-2-(tert-butylsulfamoyl)phenyl]thiazol-2-yl]cyclohexyl]carbamate(20 mg, 40 umol, 1 eq), Pd₂(dba)₃ (4 mg, 4 umol, 0.1 eq), Cs₂CO₃ (40 mg,121 umol, 3 eq) and Xantphos (2 mg, 4 umol, 0.1 eq) in dioxane (2 mL)was stirred at 110° C. for 12 h under N₂ atmosphere. The reactionmixture was concentrated and purified by prep-HPLC (column: Nano-microKromasil C18 100*40 mm 3 um; mobile phase: [water (0.1% TFA)-ACN]; B %:30%-60%,8 min) to yield isopropyltrans-N-[4-[5-[2-(tert-butylsulfamoyl)-4-(pyridazin-3-ylamino)phenyl]thiazol-2-yl]cyclohexyl]carbamate(4 mg, 6 umol, 15% yield, 100% purity) as a yellow solid. ¹H NMR (400MHz, methanol-d₄) δ=8.89 (br d, J=4.50 Hz, 1H), 8.61 (d, J=2.13 Hz, 1H),8.00 (dd, J=8.38, 2.00 Hz, 1H), 7.90 (br dd, J=9.07, 4.82 Hz, 1H), 7.79(s, 1H), 7.63 (br d, J=9.13 Hz, 1H), 7.51 (d, J=8.38 Hz, 1H), 4.78 (brs, 1H), 3.44-3.52 (m, 1H), 3.05 (ddd, J=11.94, 8.69, 3.50 Hz, 1H), 2.26(br d, J=11.88 Hz, 2H), 2.10 (br d, J=10.13 Hz, 2H), 1.67-1.79 (m, 2H),1.38-1.49 (m, 2H), 1.25 (br d, J=6.00 Hz, 6H), 1.13 (s, 9H). ESI[M+H]=573.2

Example 149 Compound Primary Screening

Primary screening was a phenotypic screen that utilized the syntheticlethal interaction between AID and RAD51 to identify compounds that wereboth potent and on target. AID expressing cells are dependent upon RAD51for survival; inhibiting RAD51 in AID positive cells results in acytotoxic effect. Based on such an effect, compounds that were potent inAID positive cells and were significantly less potent in AID negativecells were identified.

Materials and Supplies

Plastic ware and consumables needed for the experiment include: cellculture media; Evaporation Buffer media; 100% DMSO; 96 well U-bottomsterile culture plates; 250 mL bottle; 1.5 mL Opaque amber epi tubes;Epi Tube rack; 300 mL reservoirs; 25 mL reservoir; 25 mL serologicalpipette tips; 5 mL serological pipette tips P1000 Pipette Tips; and P200Pipette Tips.

Equipment needed for this experiment include: Viaflo 384 liquid handler;Eppendorf serological pipette; Eppendorf P1000 Pipette; and EppendorfP200 Pipette.

Daudi Cell Culture is also needed for this experiment. Lastly, compounds(e.g., the compounds of this application) to be tested are needed.

Procedure

All steps were performed in a sterile environment inside the Biosafetycabinet.

A 96 well u-bottom plate was prepared by writing the experiment number,plate number, date and initials in the top right corner of the platelid. With a sterile 300 ml reservoir, and 25 ml serological pipette,evaporation buffer media was pipetted into reservoir in 25 mlincrements. Using the liquid handler, 150 ul of evaporation buffer mediawas pipetted from reservoir into rows A and H, and Columns 1 and 12 ofthe 96 well u-bottom plate. Cell cultures were counted to obtain thedensity of cells per ml, and the culture viability. The cell densityinformation was used to obtain 1,000,000 cells from culture using a 5 mLserological pipette into an epi tube. The cell density information fromthe culture was used to calculate the number of cells and volume ofmedia needed for the assay to seed 1250 cells in 130 ul of media peravailable culture well in the 96 well u-bottom plate. Rows B through Fwere used for cells (50 wells in total), with row G left for an emptymedia control. The calculation was overestimated by 10 mL to account forthe dead volume in the 300 ml reservoir. Once the media volume wascalculated, the appropriate volume of media was pipetted in 25 mLincrements into the 250 mL bottle using a 25 mL serological pipette. The250 ml bottle was capped tightly, and placed into a 37° C. water bathfor 2 minutes. While the culture media was warming, 10 mL of fresh mediawas pipetted from the 500 mL culture media bottle into a sterile 25 mLreservoir. Using the Eppendorf multichannel pipette, 130 ul of media waspipetted from the 25 mL reservoir into row G of the 96 well u-bottomplate. Once the 250 mL bottle of media was warmed, the volume of cultureneeded was pipetted into the bottle, and mixed gently with a 25 mLserological pipette as to not create bubbles, and then the contents ofthe bottle were pipetted into a new 300 mL reservoir. Using the liquidhandler, 130 ul of culture was pipetted from the 300 mL reservoir intorows B through F of the 96 well u-bottom plate. Once the culture wasadded, the plate was placed into a 37° C. incubator until the compoundmaster plate was prepared for use.

Two 96 well u-bottom plates were prepared by writing the master platename in the upper right corner of the plate lid. Labeling one DMSOmaster and the other Media Master. The compounds of interest wereobtained from the laboratory freezer, and placed into a 25 well storagebox with a lid, and set the box aside. The compounds were vortexed afterthawing but before use. Using an automatic multichannel pipette, 20 ulof 100% DMSO was pipetted into wells B3-B11 through G3-G11 of the DMSOmaster plate. For each compound on the master plate, 50 ul of thecompound were pipetted in the appropriate well of row 2 (reference platemap to determine appropriate well). A serial dilution was preparedbeginning by aspirating 20 ul from row 2 and mixing with row 3,repeating until row 11 was reached. Using the liquid handler, 194 ul ofDaudi media was dispensed into wells B2-B11 through G2-G11 of the Mediamaster plate. Using the liquid handler, 6 ul from the DMSO master platewas aspirated and dispensed into the media master plate, mixing 100 ultwice.

Compounds from master plate were then added to the culture plate. Theculture plates were removed from the incubator, and set inside thebiosafety cabinet. Using a liquid handler, 20 ul from wells B2 to B11through G2 to G11 of master plate were aspirated, and dispensed intowells B2 to B11 through G2 to G11 of culture plate. This set wascontinued with each culture plate. Once the culture plates acquiredtheir 20 ul of compound dilutions, they were placed back into theincubator, until their reads on Day 7 of experiment.

Cell death was measured on Day 7 of the experiment using Cell-Titer Gloand a Promega Plate reader.

Percent cell death and EC₅₀ values were calculated by comparing the cellviability of the compound treated wells to the non-treated wells.Normalized RLU values were obtained by subtracting the media well valuesfrom each of the wells in the same column, and then dividing that valueby the DMSO treated cells values. The percent kill was then calculatedby subtracting the normalized RLU value from 1 and multiplying by 100.The average normalized percent kill value and standard error of the meanwas then calculated. The kill values were then inputted into Prism withthe corresponding standard errors. In Prism a non-linear regression linewas plotted with the data points using a semi-log scale, and the EC₅₀value was calculated. For compounds that showed good potency in theDaudi cell line, the assay was repeated using WI-38 cells (AIDnegative).

The biological activity of the compounds of the present applicationmeasured above is listed below.

TABLE 2 Cmpd No. Cellular activity in AID + (Daudi) 1 D 2 D 3 B 4 B 5 C6 C 7 C 8 B 9 C 10 B 11 C 12 D 13 B 14 C 15 C 16 C 17 C 18 C 19 D 20 C21 C 22 C 23 B 24 B 25 C 26 C 27 C 28 D 29 C 30 D 31 C 32 D 33 B 34 C 36C 38 A 40 A 41 B 42 A 44 C 45 C 46 C 48 C 49 B 50 B 51 B 52 B 54 C 56 A58 B 59 B 60 A 66 C 67 C 68 B 69 A 70 B 71 C 72 C 73 C 74 B 75 C 76 C 77C 78 C 79 A 80 B 81 B 82 B 83 B 84 B 85 B 86 B 87 B 88 B 89 B 90 B 91 B92 B 93 C 94 A 95 B 96 D 97 A 98 A 99 B 100 B 101 C 102 C 103 B 104 B105 A 106 A 107 A 108 A 109 B 110 B 111 B 112 A 113 A 114 B 115 A 116 A117 B 118 B 119 A 120 A 121 A 122 A 123 A 124 A 125 A 126 A 127 B 128 A129 A 130 B 131 A 132 B 133 C 134 B 135 B 136 A 137 A 138 B 139 A 140 B141 C 142 C 143 A 144 B 145 B 146 A 147 C 148 A 149 A 150 B 151 A 152 A153 A 154 A 155 B 156 B 157 A 158 B 159 A 160 B 161 A 162 A 163 B 164 B165 C 166 C 167 B 168 B 169 A 170 B 171 B 172 B 173 B 174 B EC₅₀: A:≤0.1 μM, B: 0.1 μM-1 μM, C: 1 μM-10 μM, D: >10 μM

EQUIVALENTS

The details of one or more embodiments of the disclosure are set forthin the accompanying description above. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present disclosure, the preferred methodsand materials are now described. Other features, objects, and advantagesof the disclosure will be apparent from the description and from theclaims. In the specification and the appended claims, the singular formsinclude plural referents unless the context clearly dictates otherwise.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. All patents and publicationscited in this specification are incorporated by reference.

The foregoing description has been presented only for the purposes ofillustration and is not intended to limit the disclosure to the preciseform disclosed, but by the claims appended hereto.

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein: thethiazolyl ring

is optionally substituted with F or Cl; the ring Cy is C₃-C₇ cycloalkyl,bridged C₆-C₁₂ cycloalkyl, or saturated heterocyclyl comprising one ortwo 3- to 7-membered rings and 1-3 heteroatoms selected from N, O, andS, wherein the cycloalkyl or heterocyclyl moiety is optionallysubstituted with one or more groups selected from halogen, OH, CN, NH₂,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy; X₁ isNR₈ or O, or, when X₁ is bonded to a nitrogen atom in the ring Cy, X₁ isabsent; X₂ is NR₈ or O; R₁ is H or C₁-C₆ alkyl optionally substitutedwith halogen, OH, C₁-C₆ alkoxy, or C₆-C₁₀ aryloxy; R₂ is H or C₁-C₆alkyl optionally substituted with halogen, OH, C₁-C₆ alkoxy, or C₆-C₁₀aryloxy; or R₁ and R₂, together with the nitrogen atom to which they areattached, form a heterocyclyl comprising one or two 3- to 7-memberedrings and 1-3 heteroatoms selected from N, O, and S; R₃ is C₁-C₆ alkyloptionally substituted with one or more groups selected from halogen,OH, and CN, phenyl, CH₂-phenyl, C₃-C₇ cycloalkyl, CH₂—(C₃-C₇)cycloalkyl, heterocyclyl, or CH₂-heterocyclyl, wherein the heterocyclylcomprises one or two 3- to 7-membered rings and 1-3 heteroatoms selectedfrom N, O, and S, wherein the cycloalkyl, phenyl, or heterocyclyl moietyis optionally substituted with one or more groups selected from halogen,OH, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄haloalkoxy; A₁, A₂, A₃, and A₄ are each independently N or C(R₄); eachR₄ is independently H, halogen, CN, OH, N(R₆′)₂, C₁-C₆ alkoxy,C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, Q-T, C₆-C₁₀ aryl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl moiety isoptionally substituted with one or more R₉; each Q is independentlyC₁-C₄ alkylene or O—(C₁-C₄) alkylene wherein the oxygen atom is bondedto the ring

each T is independently C₁-C₄ alkoxy, OH, N(R₆)₂, N(R₅)C(═O)R₆,N(R₅)C(═O)OR₆, C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the aryl or heteroarylmoiety is optionally substituted with one or more R₉; each R₅ isindependently H or C₁-C₄ alkyl; each R₆′ is independently H, C₁-C₆ alkyloptionally substituted with one or more R₇, C₁-C₆ haloalkyl, C₃-C₇cycloalkyl, heterocyclyl comprising one or two 3- to 7-membered ringsand 1-3 heteroatoms selected from N, O, and S, C₆-C₁₀ aryl, orheteroaryl comprising one or two 5- or 6-membered rings and 1-3heteroatoms selected from N, O, and S, wherein the cycloalkyl,heterocyclyl, aryl, or heteroaryl moiety is optionally substituted withone or more R₉, wherein at least one R₆′ is not H; or two R₆′ togetherwith the atoms to which they are attached form a 3- to 10-memberedheterocyclyl comprising 1-3 heteroatoms selected from N, O, and S,wherein the heterocyclyl is optionally substituted with one or more R₉;each R₆ is independently H, C₁-C₆ alkyl optionally substituted with oneor more R₇, C₁-C₆ haloalkyl, C₆-C₁₀ aryl, or heteroaryl comprising oneor two 5- or 6-membered rings and 1-3 heteroatoms selected from N, O,and S, wherein the aryl or heteroaryl moiety is optionally substitutedwith one or more R₉; or two R₆ together with the atoms to which they areattached form a 3- to 10-membered heterocyclyl comprising 1-3heteroatoms selected from N, O, and S, wherein the heterocyclyl isoptionally substituted with one or more R₉; each R₇ is independentlyN(R₈)₂, OR₈, C₆-C₁₀ aryl, or heteroaryl comprising one or two 5- or6-membered rings and 1-3 heteroatoms selected from N, O, and S; each R₅is independently H or C₁-C₆ alkyl; and each R₉ is independently oxo,halogen, OH, CN, NH₂, N(C₁-C₄ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, or C₁-C₆ haloalkoxy, wherein the C₁-C₆ alkyl is optionallysubstituted with one or more oxo, OH, O(C₁-C₄ alkyl), CN, NH₂, NH(C₁-C₄alkyl), or N(C₁-C₄ alkyl)₂.
 2. The compound of claim 1, wherein the ringCy is C₃-C₇ cycloalkyl or saturated heterocyclyl comprising one or two3- to 7-membered rings and 1-3 heteroatoms selected from N, O, and S,wherein the cycloalkyl or heterocyclyl is optionally substituted withone or more groups selected from halogen, OH, CN, NH₂, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy.
 3. The compound ofclaim 1, wherein A₁, A₂, A₃, and A₄ are each C(R₄).
 4. The compound ofclaim 1, wherein one, two, or three of A₁, A₂, A₃, and A₄ are N.
 5. Thecompound of claim 1, wherein X₁ is NR₈ and X₂ is NR₈.
 6. The compound ofclaim 1, wherein X₁ is NR₈ and X₂ is O.
 7. The compound of claim 1,wherein X₁ is O and X₂ is NR₈.
 8. The compound of claim 1, wherein X₁ isabsent and X₂ is NR₈.
 9. The compound of claim 1, wherein X₁ is absentand X₂ is O.
 10. The compound of claim 1, wherein R₃ is C₁-C₆ alkyloptionally substituted with one or more groups selected from halogen,OH, and CN.
 11. The compound of claim 1, wherein R₃ is phenyl orCH₂-phenyl, wherein the phenyl moiety is optionally substituted with oneor more groups selected from halogen, OH, CN, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, and C₁-C₄ haloalkoxy.
 12. The compound of claim1, wherein R₃ is C₃-C₇ cycloalkyl or CH₂—(C₃-C₇) cycloalkyl, wherein thecycloalkyl moiety is optionally substituted with one or more groupsselected from halogen, OH, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, and C₁-C₄ haloalkoxy.
 13. The compound of claim 1, wherein R₃ isheterocyclyl or CH₂-heterocyclyl, wherein the heterocyclyl moiety isoptionally substituted with one or more groups selected from halogen,OH, CN, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, and C₁-C₄haloalkoxy.
 14. The compound of claim 1, wherein R₁ is H.
 15. Thecompound of claim 1, wherein R₁ is C₁-C₆ alkyl optionally substitutedwith halogen, OH, C₁-C₆ alkoxy, or C₆-C₁₀ aryloxy.
 16. The compound ofclaim 1, wherein R₂ is H.
 17. The compound of claim 1, wherein R₂ isC₁-C₆ alkyl optionally substituted with halogen, OH, C₁-C₆ alkoxy, orC₆-C₁₀ aryloxy.
 18. The compound of claim 1, wherein R₁ and R₂, togetherwith the nitrogen atom to which they are attached, form a heterocyclyl.19. The compound of claim 1, wherein each R₄ is H.
 20. The compound ofclaim 1, wherein at least one R₄ is halogen, CN, OH, N(R₆′)₂, C₁-C₄alkoxy, C(═O)N(R₆)₂, C(═O)OR₆, C(═O)R₆, Q-T, C₆-C₁₀ aryl, or heteroarylcomprising one or two 5- or 6-membered rings and 1-3 heteroatomsselected from N, O, and S, wherein the aryl or heteroaryl moiety isoptionally substituted with one or more R₉.
 21. The compound of claim 1,wherein the compound is of Formula Ia, Ib, Ic, Id, Ie, If, or Ig:

or a pharmaceutically acceptable salt or solvate thereof.
 22. A compoundselected from:

or a pharmaceutically acceptable salt or solvate thereof.
 23. Thecompound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt or solvate thereof.
 24. Thecompound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt or solvate thereof.
 25. Thecompound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt or solvate thereof.
 26. Apharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier or diluent.
 27. A pharmaceuticalcomposition comprising the compound of claim 23 or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier or diluent.
 28. A pharmaceutical composition comprising thecompound of claim 24 or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier or diluent.
 29. Apharmaceutical composition comprising the compound of claim 25 or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier or diluent.
 30. A method of treatinga disease or disorder selected from cancer, an autoimmune disease, animmune deficiency, and a neurodegenerative disease, comprisingadministering to a subject in need thereof an effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt or solvatethereof, wherein treating is improving at least one symptom of thedisease or disorder.
 31. A method of treating a disease or disorderselected from cancer, an autoimmune disease, an immune deficiency, and aneurodegenerative disease, comprising administering to a subject in needthereof an effective amount of the compound of claim 23 or apharmaceutically acceptable salt or solvate thereof, wherein treating isimproving at least one symptom of the disease or disorder.
 32. A methodof treating a disease or disorder selected from cancer, an autoimmunedisease, an immune deficiency, and a neurodegenerative disease,comprising administering to a subject in need thereof an effectiveamount of the compound of claim 24 or a pharmaceutically acceptable saltor solvate thereof, wherein treating is improving at least one symptomof the disease or disorder.
 33. A method of treating a disease ordisorder selected from cancer, an autoimmune disease, an immunedeficiency, and a neurodegenerative disease, comprising administering toa subject in need thereof an effective amount of the compound of claim25 or a pharmaceutically acceptable salt or solvate thereof, whereintreating is improving at least one symptom of the disease or disorder.